U.S. patent application number 10/923464 was filed with the patent office on 2005-02-24 for chemokine inhibiting piperazine derivatives and their use to treat myocarditis.
This patent application is currently assigned to Schering Aktiegesellschaft. Invention is credited to Dole, William, Futamatsu, Hideki, Isobe, Mitsuaki, Koga, Noritaka, Suzuki, Jun-ichi.
Application Number | 20050043318 10/923464 |
Document ID | / |
Family ID | 34216121 |
Filed Date | 2005-02-24 |
United States Patent
Application |
20050043318 |
Kind Code |
A1 |
Futamatsu, Hideki ; et
al. |
February 24, 2005 |
Chemokine inhibiting piperazine derivatives and their use to treat
myocarditis
Abstract
The present invention relates to piperazine derivatives of
formulae Ia, Ib, Ic and Id and their use to treat myocarditis. 1
where R.sup.1a, R.sup.1b, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.9, R.sup.10 and Y are as defined herein.
Inventors: |
Futamatsu, Hideki; (Tokyo,
JP) ; Isobe, Mitsuaki; (Tokyo, JP) ; Koga,
Noritaka; (Tokyo, JP) ; Suzuki, Jun-ichi;
(Tokyo, JP) ; Dole, William; (Alamo, CA) |
Correspondence
Address: |
BERLEX BIOSCIENCES
PATENT DEPARTMENT
2600 HILLTOP DRIVE
P.O. BOX 4099
RICHMOND
CA
94804-0099
US
|
Assignee: |
Schering Aktiegesellschaft
Berlin
DE
Tokyo Medical and Dental University
Tokyo
JP
|
Family ID: |
34216121 |
Appl. No.: |
10/923464 |
Filed: |
August 20, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60497380 |
Aug 22, 2003 |
|
|
|
Current U.S.
Class: |
514/252.12 |
Current CPC
Class: |
A61P 25/00 20180101;
A61P 25/28 20180101; A61P 9/10 20180101; A61P 37/06 20180101; A61K
31/495 20130101; A61P 9/00 20180101; A61P 29/00 20180101; A61P
17/00 20180101; A61P 43/00 20180101; A61P 9/04 20180101; A61P 37/08
20180101; A61P 9/12 20180101 |
Class at
Publication: |
514/252.12 |
International
Class: |
A61K 031/495 |
Claims
We claim:
1. A method of treating myocarditis comprising administrating an
effective amount of at least one compound of formula Ia, Ib, Ic or
Id to a patient in need thereof 4enantiomers, diasteriomers and
pharmaceutically acceptable salts thereof wherein R.sup.1a is one
or more substituents independently selected from the group
consisting of oxo, halo, alkyl, cycloalkyl, cycloalkylalkyl,
cycloalkylaminoalkyl, (cycloalkylalkyl)aminoalkyl, haloalkyl,
alkenyl, alkynyl, aryl, aralkyl, aralkenyl, formyl, formylalkyl,
hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, (hydroxy)aralkyl,
(hydroxy)cycloalkylalkyl, mercaptoalkyl, cyanoalkyl,
haloalkylcarbonylaminoalkyl, (alkoxy)aralkyl, alkoxyalkyl,
aryloxyalkyl, aralkoxyalkyl, alkylthioalkyl, alkylsulfinylalkyl,
alkylsulfonylalkyl, hydroxyalkylthioalkyl, aminoalkyl,
monoalkylaminoalkyl, dialkylaminoalkyl, monoarylaminoalkyl,
monoaralkylaminoalkyl, alkylcarbonylaminoalkyl,
(alkylcarbonyl)(alkyl)ami- noalkyl, azidoalkyl, ureidoalkyl,
monoalkylureidoalkyl, dialkylureidoalkyl,
(alkoxycarbonylalkyl)ureidoalkyl, alkoxycarbonylaminoalkyl,
hydroxyalkylaminoalkyl, aryloxyalkylcarbonyloxy- alkyl,
alkoxyalkylcarbonyloxyalkyl, aralkoxyalkylcarbonyloxyalkyl,
alkylcarbonyl, alkylcarbonylalkyl, carboxy, alkoxycarbonyl,
aralkoxycarbonyl, aralkylcarbonyl, aminocarbonyl,
monoalkylaminocarbonyl, dialkylaminocarbonyl,
monoarylaminocarbonyl, monoaralkylaminocarbonyl, carboxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aminocarbonylalkyl,
monoalkylaminocarbonylalkyl, dialkylaminocarbonylalky- l,
monoarylaminocarbonylalkyl, monoaralkylaminocarbonylalkyl,
arylsulfonyl, heterocyclyl and heterocyclylalkyl; R.sup.2 is one or
more substituents independently selected from the group consisting
of hydrogen, hydroxy, hydroxysulfonyl, halo, alkyl, mercapto,
mercaptoalkyl, alkylthio, alkylsulfinyl, alkylsufonyl,
alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkoxy,
aryloxy, haloalkyl, formyl, formylalkyl, nitro, nitroso, cyano,
aralkoxy, haloalkoxy, cycloalkyl, cycloalkylalkyl,
(hydroxy)cycloalkylalkyl, cycloalkylamino, cycloalkylaminoalkyl,
(cycloalkylalkyl)amino, (cycloalkyalkyl)aminoalkyl, cyanoalkyl,
alkenyl, alkynyl, aryl, aralkyl, aralkenyl, hydroxyalkyl,
(hydroxy)aralkyl, hydroxyalkylthioalkyl, hydroxyalkenyl,
hydroxyalkynyl, alkoxyalkyl, (alkoxy)aralkyl, aryloxyalkyl,
aralkoxyalkyl, amino, monoalkylamino, dialkylamino, monoarylamino,
monoaralkylamino, aminoalkyl, monoalkylaminoalkyl,
dialkylaminoalkyl, hydroxyalkylaminoalkyl, monoarylaminoalkyl,
monoaralkylaminoalkyl, alkylcarbonylamino,
(alkylcarbonyl)(alkyl)amino, alkylcarbonylaminoalkyl,
(alkylcarbonyl)(alkyl)aminoalkyl, alkoxycarbonylamino,
(alkoxycarbonyl)(alkyl)amino, alkoxycarbonylaminoalkyl,
(alkoxycarbonyl)(alkyl)aminoalkyl, carboxy, alkoxycarbonyl,
aralkoxycarbonyl, alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl,
arylcarbonylalkyl, aralkylcarbonyl, aralkylcarbonylalkyl,
carboxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
alkoxyalkylcarbonyloxyalkyl, aminocarbonyl, monoalkylaminocarbonyl,
dialkylaminocarbonyl, monoarylaminocarbonyl,
monoaralkylaminocarbonyl, aminocarbonylalkyl,
monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl,
monoarylaminocarbonylalkyl, monoaralkylaminocarbonylalkyl, amidino,
guanidino, ureido, monoalkylureido, dialkylureido, ureidoalkyl,
monoalkylureidoalkyl, dialkylureidoalkyl, heterocyclyl and
heterocyclylalkyl; R.sup.3 is a carbocylic ring system substituted
by one or more substituents independently selected from the group
consisting of hydrogen, hydroxy, hydroxysulfonyl, halo, alkyl,
mercapto, mercaptoalkyl, alkylthio, alkylsulfinyl, alkylsufonyl,
arylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl,
alkylsulfonylalkyl, alkoxy, hydroxyalkoxy, aryloxy, haloalkyl,
formyl, formylalkyl, nitro, nitroso, cyano, aralkoxy, haloalkoxy,
aminoalkoxy, cycloalkyl, cycloalkylalkyl, (hydroxy)cycloalkylalkyl,
cycloalkylamino, cycloalkylaminoalkyl, cyanoalkyl, alkenyl,
alkynyl, aryl, aralkyl, aralkenyl, hydroxyalkyl, (hydroxy)aralkyl,
(monoalkylamino)aralkyl, (hydroxyalkyl)hioalkyl, hydroxyalkenyl,
hydroxyalkynyl, alkoxyalkyl, (alkoxy)araikyl, aryloxyalkyl,
aralkoxyalky, amino, monoalkylamlno, dialkyamino, monoarylamino,
monoaralkylamino, aminoalkylamino, heterocyclylamino,
(cycloalkylalkyl)amino, alkylcarbonylamino, alkoxycarbonylamino,
alkenylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino,
heterocyclylcarbonylamino, haloalkylcarbonylamino,
alkoxyalkylcarbonylamino, alkoxycarbonylalkylcarbonylamino,
(alkylcarbonyl)(alkyl)amino, (alkoxycarbonyl)(alkyl)amino,
alkylsulfonylamino, aminoalkyl, monoalkylaminoalkyl,
dialkylaminoalkyl, hydroxyalkylaminoalkyl, monoarylaminoalkyl,
monoaralkylaminoalkyl, alkylcarbonylaminoalkyl,
arylcarbonylaminoalkyl, (alkylcarbonyl)(alkyl)am- inoalkyl,
(cycloalkyalkyl)aminoalkyl, alkoxycarbonylaminoalkyl,
alkoxycarbonylalkylcarbonylaminoalkyl,
(alkoxycarbonyl)(alkyl)aminoalkyl, alkylsulfonylaminoalkyl,
(alkylsulfonyl)(alkyl)aminoalkyl, arylsulfonylaminoalkyl,
(arylsulfonyl)(alkyl)aminoalkyl, heterocyclylaminoalkyl, carboxy,
alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, arylcarbonyl,
aralkylcarbonyl, (hydroxyalkoxy)carbonyl, carboxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
alkoxyalkylcarbonyloxyalkyl, dialkylaminocarbonyloxyalkyl,
alkylcarbonylalkyl, arylcarbonylalkyl, aralkylcarbonylalkyl,
aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl,
monoarylaminocarbonyl, monoaralkylaminocarbonyl,
(aminocarbonylalkyl)amin- ocarbonyl,
(monoalkylaminocarbonylalkyl)aminocarbonyl,
(carboxyalkyl)aminocarbonyl, (alkoxycarbonylalkyl)aminocarbonyl,
(aminoalkyl)aminocarbonyl, (hydroxyalkyl)aminocarbonyl,
aminocarbonylalkyl, monoalkylaminocarbonylalkyl,
dialkylaminocarbonylalky- l, monoarylaminocarbonylalkyl,
monoaralkylaminocarbonylalkyl, amidino, hydroxyamidino, guanidino,
ureido, monoalkylureido, monoarylureido, monoaralkylureido,
monohaloalkylureido, (monoalkyl)(monoaryl)ureido, dialkylureido,
diarylureido, (haloalkylcarbonyl)ureido, ureidoalkyl,
monoalkylureidoalkyl, dialkylureidoalkyl, monoarylureidoalkyl,
monoaralkylureidoalkyl, monohaloalkylureidoalkyl,
(haloalkyl)(alkyl)ureid- oalkyl, (alkoxycarbonylalkyl)ureidoalkyl,
glycinamido, monoalkylglycinamido, aminocarbonylglycinamido,
(alkoxyalkylcarbonyl)glyc- inamido,
(aminocarbonyl)(alkyl)glycinamido, (alkoxycarbonylalkylcarbonyl)(-
alkyl)glycinamido, (alkoxycarbonylaminoalkylcarbonyl)glycinamido,
arylcarbonylglycinamido, (aryicarbonyl)(alkyl)glycinamido,
(monoaralkylaminocarbonyl)glycinamido,
(monoaralkylaminocarbonyl)(alkyl)g- lycinamido,
(monoarylaminocarbonyl)glycinamido, (monoarylaminocarbonyl)(al-
kyl)glycinamido, glycinamidoalkyl, alaninamido,
monoalkylalaninamido, alaninamidoalkyl, heterocyclyl and
heterocyclylalkyl; or R.sup.3 is a heterocyclic ring system
substituted by one or more substituents independently selected from
the group consisting of hydrogen, hydroxy, halo, alkyl,
alkylsufonyl, arylsulfonyl, alkoxy, hydroxyalkoxy, haloalkyl,
formyl, nitro, cyano, haloalkoxy, alkenyl, alkynyl, aryl, aralkyl,
amino, monoalkylamino, dialkylamino, monoarylamino,
monoaralkylamino, alkylcarbonylamino, alkoxycarbonylamino,
alkenylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino,
haloalkylcarbonylamino, alkoxyalkylcarbonylamino,
alkoxycarbonylalkylcarb- onylamino, (alkylcarbonyl)(alkyl)amino,
(alkoxycarbonyl)(alkyl)amino, alkylsulfonylamino, aminoalkyl,
monoalkylaminoalkyl, dialkylaminoalkyl, alkylcarbonylaminoalkyl,
arylcarbonylaminoalkyl, (alkylcarbonyl)(alkyl)am- inoalkyl,
alkoxycarbonylaminoalkyl, carboxy, alkoxycarbonyl,
aralkoxycarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl,
aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl,
monoarylaminocarbonyl, aminocarbonylalkyl,
monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl,
monoarylaminocarbonylalkyl, guanidino, ureido, monoalkylureido,
ureidoalkyl, monoalkylureidoalkyl, and glycinamido; R.sup.4 is
--O--, --N(R.sup.7)--, --C(R.sup.8).sub.2-- or a bond; R.sup.5 is
an alkylene chain or an alkylidene chain, or, if R.sup.4 is a bond,
R.sup.5 is an alkylidene chain optionally substituted by aryl or
--N(R.sup.7).sub.2; R.sup.6 is --C(O)--, --C(S)--, --CH.sub.2-- or
a bond; each R.sup.7 is independently selected from the group
consisting of hydrogen, alkyl, aryl, aralkyl, alkylcarbonyl,
alkylcarbonylalkyl, aralkylcarbonyl, aralkylcarbonylalkyl,
aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, and
alkoxycarbonyl; and each R.sup.8 is independently selected from the
group consisting of hydrogen, alkyl, aryl, aralkyl, hydroxy,
alkoxy, hydroxyalkyl, alkoxyalkyl, amino, monoalkylamino,
dialkylamino, alkylcarbonylamino, cycloalkylcarbonylamino,
cycloalkylalkylcarbonylamino, alkoxycarbonylamino,
alkylsulfonylamino, arylcarbonylamino,
alkoxycarbonylalkylcarbonylamino, (alkylcarbonyl)(alkyl)amino,
aralkylcarbonylamino, (aralkylcarbonyl)(alkyl)amino,
alkylcarbonylaminoalkyl, cycloalkylcarbonylaminoalkyl,
alkoxycarbonylaminoalkyl, (alkylcarbonyl)(alkyl)aminoalkyl,
aralkylcarbonylaminoalkyl, heterocyclylcarbonylaminoalkyl,
(aralkylcarbonyl)(alkyl)aminoalkyl, arylsulfonylamino,
alkylsulfonylaminoalkyl, ureido, monoalkylureido,
monohaloalkylureido, dialkylureido, ureidoalkyl,
monoalkylureidoalkyl, dialkylureidoalkyl, monohaloalkylureidoalkyl,
aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl,
alkoxycarbonylalkyl, aminocarbonylalkyl,
monoalkylaminocarbonylalkyl, and dialkylaminocarbonylalkyl; Y is a
pharmaceutically acceptable counterion: R.sup.1b is one or more
substituents independently selected from the group consisting of
hydrogen, oxo, halo, alkyl, cycloalkyl, cycloalkylalkyl,
cycloalkylaminoalkyl, (cycloalkylalkyl)aminoalkyl, haloalkyl,
alkenyl, alkynyl, aryl, aralkyl, aralkenyl, formyl, formylalkyl,
hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, (hydroxy)aralkyl,
(hydroxy)cycloalkylalky- l, mercaptoalkyl, cyanoalkyl,
haloalkylcarbonylaminoalkyl, (alkoxy)aralkyl, alkoxyalkyl,
aryloxyalkyl, aralkoxyalkyl, alkylthioalkyl, alkylsulfinylalkyl,
alkylsulfonylalkyl, hydroxyalkylthioalkyl, aminoalkyl,
monoalkylaminoalkyl, dialkylaminoalkyl, monoarylaminoalkyl,
monoaralkylaminoalkyl, alkylcarbonylaminoalkyl,
(alkylcarbonyl)(alkyl)aminoalkyl, azidoalkyl, ureidoalkyl,
monoalkylureidoalkyl, dialkylureidoalkyl,
(alkoxycarbonylalkyl)ureidoalkyl, alkoxycarbonylaminoalkyl,
hydroxyalkylaminoalkyl, aryloxyalkylcarbonyloxyalkyl,
alkoxyalkylcarbonyloxyalkyl, aralkoxyalkylcarbonyloxyalkyl,
alkylcarbonyl, alkylcarbonylalkyl, carboxy, alkoxycarbonyl,
aralkoxycarbonyl, aralkylcarbonyl, aminocarbonyl,
monoalkylaminocarbonyl, dialkylaminocarbonyl,
monoarylaminocarbonyl, monoaralkylaminocarbonyl, carboxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aminocarbonylalkyl,
monoalkylaminocarbonylalkyl, dialkylaminocarbonylalky- l,
monoarylaminocarbonylalkyl, monoaralkylaminocarbonylalkyl,
arylsulfonyl, heterocyclyl and heterocyclylalkyl; and R.sup.9 is
alkyl, aralkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl,
alkoxycarbonylalkyl, alkylcarbonylalkyl, alkylcarbonylaminoalkyl,
aminocarbonylalkyl, monoalkylaminocarbonylalkyl,
dialkylaminocarbonylalky- l, hetereocyclylalkyl, or
cycloalkylalkyl; R.sup.10 is a heterocyclyl optionally substituted
by one or more substituents selected from the group consisting of
hydroxy, mercapto, halo, alkyl, alkenyl, alkynyl, phenyl,
phenylalkyl, phenylalkenyl, alkoxy, phenoxy, phenylalkoxy,
haloalkyl, haloalkoxy, formyl, nitro, cyano, amidino, cycloalkyl,
hydroxyalkyl, alkoxyalkyl, phenoxyalkyl, phenylalkoxyalkyl, amino,
monoalkylamino, dialkylamino, monophenylamino,
monophenylalkylamino, aminoalkyl, monoalkylaminoalkyl,
dialkylaminoalkyl, monophenylaminoalkyl, monophenylalkylaminoalkyl,
carboxy, alkoxycarbonyl, phenylcarbonyl, benzylcarbonyl,
alkylcarbonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl,
monoalkylaminocarbonyl, dialkylaminocarbonyl, phenylaminocarbonyl,
aminocarbonylalkyl, monoalkylaminocarbonylalkyl,
dialkylaminocarbonylalkyl, ureido, monoalkylureido,
monophenylureido, and monobenzylureido; provided that when R.sup.4
is --N(R.sup.7)--, R.sup.3 can not be a heterocyclic ring system
containing 4-8 members consisting of carbon atoms and only one
nitrogen atom.
2. A method of claim 1 wherein the compound is a compound of
formula Ia.
3. A method of claim 2 wherein R.sup.3 is a carbocylic ring system
substituted by one or more substituents independently selected from
the group consisting of hydrogen, hydroxy, hydroxysulfonyl, halo,
alkyl, mercapto, mercaptoalkyl, alkylthio, alkylsulfinyl,
alkylsufonyl, arylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl,
alkylsulfonylalkyl, alkoxy, hydroxyalkoxy, aryloxy, haloalkyl,
formyl, formylalkyl, nitro, nitroso, cyano, aralkoxy, haloalkoxy,
aminoalkoxy, cycloalkyl, cycloalkylalkyl, (hydroxy)cycloalkylalkyl,
cycloalkylamino, cycloalkylaminoalkyl, cyanoalkyl, alkenyl,
alkynyl, aryl, aralkyl, aralkenyl, hydroxyalkyl, (hydroxy)aralkyl,
(monoalkylamino)aralkyl, (hydroxyalkyl)hioalkyl, hydroxyalkenyl,
hydroxyalkynyl, alkoxyalkyl, (alkoxy)aralkyl, aryloxyalkyl,
aralkoxyalkyl, amino, monoalkylamino, dialkylamino, monoarylamino,
monoaralkylamino, aminoalkylamino, heterocyclylamino,
(cycloalkylalkyl)amino, alkylcarbonylamino, alkoxycarbonylamino,
alkenylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino,
heterocyclylcarbonylamino, haloalkylcarbonylamino,
alkoxyalkylcarbonylamino, alkoxycarbonylalkylcarbonylamino,
(alkylcarbonyl)(alkyl)amino, (alkoxycarbonyl)(alkyl)amino,
alkylsulfonylamino, aminoalkyl, monoalkylaminoalkyl,
dialkylaminoalkyl, hydroxyalkylaminoalkyl, monoarylaminoalkyl,
monoaralkylaminoalkyl, alkylcarbonylaminoalkyl,
arylcarbonylaminoalkyl, (alkylcarbonyl)(alkyl)am- inoalkyl,
(cycloalkyalkyl)aminoalkyl, alkoxycarbonylaminoalkyl,
alkoxycarbonylalkylcarbonylaminoalkyl,
(alkoxycarbonyl)(alkyl)aminoalkyl, alkylsulfonylaminoalkyl,
(alkylsulfonyl)(alkyl)aminoalkyl, arylsulfonylaminoalkyl,
(arylsulfonyl)(alkyl)aminoalkyl, heterocyclylaminoalkyl, carboxy,
alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, arylcarbonyl,
aralkylcarbonyl, (hydroxyalkoxy)carbonyl, carboxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
alkoxyalkylcarbonyloxyalkyl, dialkylaminocarbonyloxyalkyl,
alkylcarbonylalkyl, arylcarbonylalkyl, aralkylcarbonylalkyl,
aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl,
monoarylaminocarbonyl, monoaralkylaminocarbonyl,
(aminocarbonylalkyl)amin- ocarbonyl,
(monoalkylaminocarbonylalkyl)aminocarbonyl,
(carboxyalkyl)aminocarbonyl, (alkoxycarbonylalkyl)aminocarbonyl,
(aminoalkyl)aminocarbonyl, (hydroxyalkyl)aminocarbonyl,
aminocarbonylalkyl, monoalkylaminocarbonylalkyl,
dialkylaminocarbonylalky- l, monoarylaminocarbonylalkyl,
monoaralkylaminocarbonylalkyl, amidino, hydroxyamidino, guanidino,
ureido, monoalkylureido, monoarylureido, monoaralkylureido,
monohaloalkylureido, (monoalkyl)(monoaryl)ureido, dialkylureido,
diarylureido, (haloalkylcarbonyl)ureido, ureidoalkyl,
monoalkylureidoalkyl, dialkylureidoalkyl, monoarylureidoalkyl,
monoaralkylureidoalkyl, monohaloalkylureidoalkyl,
(haloalkyl)(alkyl)ureid- oalkyl, (alkoxycarbonylalkyl)ureidoalkyl,
glycinamido, monoalkylglycinamido, aminocarbonylglycinamido,
(alkoxyalkylcarbonyl)glyc- inamido,
(aminocarbonyl)(alkyl)glycinamido, (alkoxycarbonylalkylcarbonyl)(-
alkyl)glycinamido, (alkoxycarbonylaminoalkylcarbonyl)glycinamido,
arylcarbonylglycinamido, (arylcarbonyl)(alkyl)glycinamido,
(monoaralkylaminocarbonyl)glycinamido,
(monoaralkylaminocarbonyl)(alkyl)g- lycinamido,
(monoarylaminocarbonyl)glycinamido, (monoarylaminocarbonyl)(al-
kyl)glycinamido, glycinamidoalkyl, alaninamido,
monoalkylalaninamido, alaninamidoalkyl, heterocyclyl and
heterocyclylalkyl.
4. A method of claim 3 wherein R.sup.4 is --O--, --N(R.sup.7)-- or
--C(R.sup.8)--; R.sup.5 is an alkylene chain; R.sup.7 is selected
from the group consisting of hydrogen, alkyl, aryl, aralkyl,
alkylcarbonyl, alkylcarbonylalkyl, aralkylcarbonyl,
aralkylcarbonylalkyl, aminocarbonyl, monoalkylaminocarbonyl,
dialkylaminocarbonyl, and alkoxycarbonyl; and each R.sup.8 is
independently selected from the group consisting of hydrogen,
alkyl, aryl, aralkyl, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl,
amino, monoalkylamino, dialkylamino, alkylcarbonylamino,
cycloalkylcarbonylamino, cycloalkylalkylcarbonylamino,
alkoxycarbonylamino, alkylsulfonylamino, arylcarbonylamino,
alkoxycarbonylalkylcarbonylamino, (alkylcarbonyl)(alkyl)amino,
aralkylcarbonylamino, (aralkylcarbonyl)(alkyl)amino,
alkylcarbonylaminoalkyl, cycloalkylcarbonylaminoalkyl,
alkoxycarbonylaminoalkyl, (alkylcarbonyl)(alkyl)aminoalkyl,
aralkylcarbonylaminoalkyl, heterocyclylcarbonylaminoalkyl,
(aralkylcarbonyl)(alkyl)aminoalkyl, arylsulfonylamino,
alkylsulfonylaminoalkyl, ureido, monoalkylureido,
monohaloalkylureido, dialkylureido, ureidoalkyl,
monoalkylureidoalkyl, dialkylureidoalkyl, monohaloalkylureidoalkyl,
aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl,
alkoxycarbonylalkyl, aminocarbonylalkyl,
monoalkylaminocarbonylalkyl, and dialkylaminocarbonylalkyl.
5. A method of claim 4 wherein R.sup.4 is --O--; R.sup.5 is
methylene; and R.sup.6 is --C(O)--.
6. A method of claim 5 wherein R.sup.1a is one or more substituents
independently selected from the group consisting of halo, alkyl,
cycloalkyl, cycloalkylaminoalkyl, haloalkyl, hydroxyalkyl,
hydroxyalkenyl, hydroxyalkynyl, (hydroxy)aralkyl, cyanoalkyl,
haloalkylcarbonylaminoalkyl, alkoxyalkyl, aralkoxyalkyl,
alkylthioalkyl, hydroxyalkylthioalkyl, aminoalkyl,
monoalkylaminoalkyl, dialkylaminoalkyl, monoarylaminoalkyl,
monoaralkylaminoalkyl, azidoalkyl, monoalkylureidoalkyl,
(alkoxycarbonylalkyl)ureidoalkyl, hydroxyalkylaminoalkyl,
aryloxyalkylcarbonyloxyalkyl, aralkoxyalkylcarbonyloxyalkyl,
alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, and
heterocyclylalkyl; R.sup.2 is one or more substituents
independently selected from the group consisting of hydrogen and
halo; R.sup.3 is phenyl optionally substituted by one or more
substituents independently selected from the group consisting of
hydrogen, hydroxy, halo, alkyl, alkoxy, hydroxyalkoxy, haloalkyl,
formyl, nitro, cyano, aminoalkoxy, cycloalkyl,
cycloalkylaminoalkyl, aralkyl, hydroxyalkyl,
(monoalkylamino)aralkyl, alkoxyalkyl, amino, monoalkylamino,
dialkylamino, monoaralkylamino, alkylcarbonylamino,
alkenylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino,
heterocyclylcarbonylamino, haloalkylcarbonylamino,
alkoxyalkylcarbonylamino, alkoxycarbonylalkylcarbonylamino,
(alkylcarbonyl)(alkyl)amino, alkylsulfonylamino, aminoalkyl,
monoalkylaminoalkyl, dialkylaminoalkyl, monoarylaminoalkyl,
monoaralkylaminoalkyl, alkylcarbonylaminoalkyl,
arylcarbonylaminoalkyl, (alkylcarbonyl)(alkyl)aminoalkyl,
(cycloalkyalkyl)aminoalkyl, alkoxycarbonylaminoalkyl,
alkoxycarbonylalkylcarbonylaminoalkyl,
(alkoxycarbonyl)(alkyl)aminoalkyl, alkylsulfonylaminoalkyl,
(alkylsulfonyl)(alkyl)aminoalkyl, arylsulfonylaminoalkyl,
(arylsulfonyl)(alkyl)aminoalkyl, heterocyclylaminoalkyl, carboxy,
alkoxycarbonyl, alkylcarbonyl, (hydroxyalkoxy)carbonyl,
aminocarbonyl, monoalkylaminocarbonyl, monoarylaminocarbonyl,
(aminocarbonylalkyl)aminoc- arbonyl, (aminoalkyl)aminocarbonyl,
(hydroxyalkyl)aminocarbonyl, dialkylaminocarbonylalkyl,
hydroxyamidino, ureido, monoalkylureido, monoarylureido,
monoaralkylureido, (monoalkyl)(monoaryl)ureido,
(haloalkylcarbonyl)ureido, ureidoalkyl, monoalkylureidoalkyl,
dialkylureidoalkyl, monoarylureidoalkyl, monoaralkylureidoalkyl,
monohaloalkylureidoalkyl, (haloalkyl)(alkyl)ureidoalkyl,
(alkoxycarbonylalkyl)ureidoalkyl, glycinamido,
monoalkylglycinamido, aminocarbonylglycinamido,
(alkoxyalkylcarbonyl)glycinamido,
(aminocarbonyl)(alkyl)glycinamido,
(alkoxycarbonylalkylcarbonyl)(alkyl)gl- ycinamido,
(alkoxycarbonylaminoalkyicarbonyl)glycinamido,
aryicarbonylglycinamido, (arylcarbonyl)(alkyl)glycinamido,
(monoaralkylaminocarbonyl)glycinamido,
(monoaralkylaminocarbonyl)(alkyl)g- lycinamido,
(monoarylaminocarbonyl)glycinamido, (monoarylaminocarbonyl)(al-
kyl)glycinamido, alaninamido, heterocyclyl and
heterocyclylalkyl.
7. A method of claim 6 wherein R.sup.1a is one or more substituents
independently selected from the group consisting of alkyl,
cycloalkyl, hydroxyalkyl, hydroxyalkenyl, cyanoalkyl, alkoxyalkyl,
monoalkylaminoalkyl, azidoalkyl, monoalkylureidoalkyl,
aryloxyalkylcarbonyloxyalkyl, and heterocyclylalkyl; R.sup.2 is one
or more substituents independently selected from the group
consisting of hydrogen, chloro or fluoro; R.sup.3 is phenyl
substituted by one or more substituents independently selected from
the group consisting of hydroxy, halo, alkyl, alkoxy, formyl,
nitro, cyano, aminoalkoxy, cycloalkylaminoalkyl, hydroxyalkyl,
(monoalkylamino)aralkyl, alkoxyalkyl, amino, monoalkylamino,
dialkylamino, monoaralkylamino, alkylcarbonylamino,
alkenylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino,
heterocyclylcarbonylamino, haloalkylcarbonylamino,
alkoxyalkylcarbonylamino, alkoxycarbonylalkylcarbonylamino,
alkylsulfonylamino, aminoalkyl, monoalkylaminoalkyl,
dialkylaminoalkyl, monoaralkylaminoalkyl, alkylcarbonylaminoalkyl,
arylcarbonylaminoalkyl, (alkylcarbonyl)(alkyl)aminoalkyl,
(cycloalkyalkyl)aminoalkyl, alkoxycarbonylalkylcarbonylaminoalkyl,
alkylsulfonylaminoalkyl, (alkylsulfonyl)(alkyl)aminoalkyl,
arylsulfonylaminoalkyl, (arylsulfonyl)(alkyl)aminoalkyl, carboxy,
alkoxycarbonyl, alkylcarbonyl, (hydroxyalkoxy)carbonyl,
aminocarbonyl, monoalkylaminocarbonyl, monoarylaminocarbonyl,
(aminocarbonylalkyl)aminocarbonyl, (aminoalkyl)aminocarbonyl,
(hydroxyalkyl)aminocarbonyl, hydroxyamidino, ureido,
monoalkylureido, monoarylureido, monoaralkylureido,
(monoalkyl)(monoaryl)ureido, (haloalkylcarbonyl)ureido,
ureidoalkyl, monoalkylureidoalkyl, dialkylureidoalkyl,
monoarylureidoalkyl, monoaralkylureidoalkyl,
monohaloalkylureidoalkyl, (haloalkyl)(alkyl)ureid- oalkyl,
(alkoxycarbonylalkyl)ureidoalkyl, glycinamido,
monoalkylglycinamido, aminocarbonylglycinamido,
(alkoxyalkylcarbonyl)glyc- inamido,
(aminocarbonyl)(alkyl)glycinamido, (alkoxycarbonylalkylcarbonyl)(-
alkyl)glycinamido, (alkoxycarbonylaminoalkylcarbonyl)glycinamido,
arylcarbonylglycinamido, (arylcarbonyl)(alkyl)glycinamido,
(monoaralkylaminocarbonyl)(alkyl)glycinamido,
(monoarylaminocarbonyl)glyc- inamido,
(monoarylaminocarbonyl)(alkyl)glycinamido, alaninamido,
heterocyclyl and heterocyclylalkyl.
8. A method of claim 7 wherein R.sup.1a is one or more substituents
independently selected from the group consisting of alkyl and
hydroxyalkyl; R.sup.2 is one or more substituents independently
selected from the group consisting of hydrogen, chloro or fluoro;
R.sup.3 is phenyl substituted by one or more substituents
independently selected from the group consisting of halo, alkyl,
alkoxy, formyl, nitro, cycloalkylaminoalkyl, hydroxyalkyl, amino,
alkylcarbonylamino, haloalkylcarbonylamino,
alkoxyalkylcarbonylamino, alkoxycarbonylalkylcarb- onylamino,
alkylsulfonylamino, aminoalkyl, monoalkylaminoalkyl,
dialkylaminoalkyl, (alkylsulfonyl)(alkyl)aminoalkyl, alkylcarbonyl,
aminocarbonyl, monoalkylaminocarbonyl, monoarylaminocarbonyl,
(aminocarbonylalkyl)aminocarbonyl, (aminoalkyl)aminocarbonyl,
hydroxyamidino, ureido, (haloalkylcarbonyl)ureido, ureidoalkyl,
glycinamido, monoalkylglycinamido, aminocarbonylglycinamido,
(alkoxyalkylcarbonyl)glycinamido,
(aminocarbonyl)(alkyl)glycinamido,
(alkoxycarbonylaminoalkylcarbonyl)glycinamido, alaninamido, and
heterocyclylalkyl.
9. A method of claim 8 wherein R.sup.2 is 4-fluoro and R.sup.3 is
phenyl substituted at the 4-position with chloro and at the
2-position by aminocarbonyl, ureido, or glycinamido.
10. A method of claim 9 wherein the compound is selected from
(2R,5S)-1-((4-chloro-2-(aminocarbonyl)phenoxy)methyl)carbonyl-2,5-dimethy-
l4-(4-fluorobenzyl)piperazine;
(trans)-1-((4-chloro-2-(giycinamido)phenoxy-
)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
(2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl4-(4-fluorobe-
nzyl)piperazine;
(trans)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2,-
5-dimethyl-4-(4-fluorobenzyl)piperazine;
(2R,5S)-1-((4-chloro-2-(ureido)ph-
enoxy)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
and
(2R,5S)-1-((4-chloro-2-(glycinamido)phenoxy)methyl)carbonyl-2,5-dimethyl--
4-(4-fluorobenzyl)piperazine enantiomers, diastereomers, salts and
solvates thereof.
11. A method of claim 10 wherein the compound is
(2R)-1-((4-chloro-2-(urei-
do)phenoxy)methyl)carbonyl-2-methyl4-(4-fluorobenzyl)piperazine
enantiomers, diastereomers, salts and solvates thereof.
12. A method of claim 1 wherein the compound of formula Ia, Ib, Ic
or Id is administered in combination with at least one additional
therapeutic agent selected from Diuretics; ACE Inhibitors;
Angiotensin Receptor Antagonists; Beta Adrenoreceptor Blockers;
Carvedilol and Labetolol; Vasodilators; and Positive Inotropic
Agents.
Description
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 60/497,380, filed Aug. 22, 2003, which is
incorporated herein in full by reference.
FIELD OF THE INVENTION
[0002] The present invention is directed to the use of piperazine
derivatives to treat myocarditis.
BACKGROUND OF THE INVENTION
[0003] Myocarditis is an inflammatory process involving the heart
often caused by an infectious agent. In North America and Europe,
viruses are the most common cause, whereas in Central and South
America, the parasitic protozoan Trypanosoma cruzi is more common
and accounts for the majority of cases of myocarditis worldwide.
Virtually any infectious agent can cause myocarditis. Other causes
include drugs, toxins, allergic reactions, and certain systemic
diseases associated with vasculitis. While myocarditis is an
insidious process and is usually asymptomatic, it can result in
heart failure and postmortum studies suggest that myocarditis may
account for up to 20% of cases of sudden, unexpected death in young
adults. Recent data has also further strengthened the suspected
causal link between viral myocarditis and later development of
idiopathic dilated cardiomyopathy.
[0004] Current understanding of the basic mechanisms of myocarditis
derives largely from experimental models in which mice are infected
with a cardiotropic virus. The primary mechanism for cardiac damage
in myocarditis is thought to be a cell mediated immunological
reaction to antigens associated with the pathogenic agent itself or
to changes in the myocyte cell surface induced by the agent.
Humoral autoimmunity has also been shown to also be involved. The
initial cellular response is characterized by infiltration of
natural killer cells and macrophages with subsequent release of
pro-inflammatory cytokines including interleukins 1and 2, tumor
necrosis factor and interferon gamma. Later in the course of
experimental myocarditis, cytotoxic T lymphocytes can be found as
well as B lymphocytes with production of anti-myocardial
antibodies.
[0005] Findings in patients with myocarditis further support
immunologic mechanisms for the observed cardiac damage and
subsequent development of heart failure. These include: an
imbalance between cytotoxic and helper T cells; increased
myocardial expression of major histocompatibility antigens in
biopsy specimens; overexpression of cell adhesion molecules on
myocytes; and circulating autoantibodies directed against
myocardial proteins some of which cross react with viral antigens
(molecular mimicry). The effects of the immune reaction in the
heart will depend on whether the response is self limited resulting
in effective clearance of the etiologic agent and repair of cardiac
injury or whether the response is prolonged and exaggerated
resulting in progressive myocyte necrosis, fibrosis and pathologic
remodeling.
[0006] The clinical features of myocarditis are quite variable.
Most patients with focal inflammation are relatively asymptomatic
and may demonstrate only minor electrocardiographic abnormalities.
Others with more extensive inflammation can present with
ventricular dilatation and mild to moderate heart failure. A
smaller subset of patients manifest rapidly progressive dilated
cardiomyopathy and severe, fulminant heart failure. Still others
will present with atrial or ventricular arrhythmias, or
atrio-ventricular heart block.
[0007] Treatment of myocarditis is largely supportive and directed
at the systemic manifestations of the disease. All patients with
suspected myocarditis and signs and symptoms of heart failure
should be hospitalized and treated in a unit equipped with
continuous electrocardiographic monitoring. Treatment of heart
failure includes use of diuretics, angiotensin converting enzyme
inhibitors or receptor antagonists, and beta-blockers after initial
patient stabelization. In patients with moderate to severe heart
faiure, supportive care may include use of parenteral inotropic and
vasodilator drugs and possibly implantation of a temporary
mechanical ventricular assist device. Antiarrhythmic drugs may be
needed to suppress serious atrial or ventricular arrhythmias and a
pacemaker may be required in cases of complete heart block. Since
the long term consequences of myocarditis are attributed to an
exaggerated cellular and humoral immune reaction, immunosuppressive
and anti-inflammatory drugs could be of benefit. While uncontrolled
clinical studies of immunosuppressive agents supports such an
approach, to date, placebo controlled trials of prednisone alone
and in combination with cyclosporine and of intravenous immune
globulin have failed to demonsrate a beneficial effect on
ventricular function. It is hoped that better understanding of the
etiologic agents and immune response in myocarditis will lead to
more selective pharmacologic approaches to prevent progressive
heart failure and development of dilated cardiomyopathy in the near
future.
[0008] Piperazine derivatives of formulae Ia, Ib, Ic and Id are
disclosed in U.S. Pat. No. 6,207,665 and WO 98/56771 (the entirety
of each of these documents is incorporated herein by reference) as
being useful as anti-inflamatory agents in view of their ability to
inhibit chemokines, MIP-1.alpha. and RANTES: 2
[0009] enantiomers, diasteriomers and pharmaceutically acceptable
salts thereof wherein:
[0010] R.sup.1a is one or more substituents independently selected
from the group consisting of oxo, halo, alkyl, cycloalkyl,
cycloalkylalkyl, cycloalkylaminoalkyl, (cycloalkylalkyl)aminoalkyl,
haloalkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, formyl,
formylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl,
(hydroxy)aralkyl, (hydroxy)cycloalkylalky- l, mercaptoalkyl,
cyanoalkyl, haloalkylcarbonylaminoalkyl, (alkoxy)aralkyl,
alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthioalkyl,
alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkylthioalkyl,
aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,
monoarylaminoalkyl, monoaralkylaminoalkyl, alkylcarbonylaminoalkyl,
(alkylcarbonyl)(alkyl)aminoalkyl, azidoalkyl, ureidoalkyl,
monoalkylureidoalkyl, dialkylureidoalkyl,
(alkoxycarbonylalkyl)ureidoalkyl, alkoxycarbonylaminoalkyl,
hydroxyalkylaminoalkyl, aryloxyalkylcarbonyloxyalkyl,
alkoxyalkylcarbonyloxyalkyl, aralkoxyalkylcarbonyloxyalkyl,
alkylcarbonyl, alkylcarbonylalkyl, carboxy, alkoxycarbonyl,
aralkoxycarbonyl, aralkylcarbonyl, aminocarbonyl,
monoalkylaminocarbonyl, dialkylaminocarbonyl,
monoaryiaminocarbonyl, monoaralkylaminocarbonyl, carboxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aminocarbonylalkyl,
monoalkylaminocarbonylalkyl, dialkylaminocarbonylalky- l,
monoarylaminocarbonylalkyl, monoaralkylaminocarbonylalkyl,
arylsulfonyl, heterocyclyl and heterocyclylalkyl;
[0011] R.sup.2 is one or more substituents independently selected
from the group consisting of hydrogen, hydroxy, hydroxysulfonyl,
halo, alkyl, mercapto, mercaptoalkyl, alkylthio, alkylsulfinyl,
alkylsufonyl, alkylthioalkyl, alkylsulfinylalkyl,
alkylsulfonylalkyl, alkoxy, aryloxy, haloalkyl, formyl,
formylalkyl, nitro, nitroso, cyano, aralkoxy, haloalkoxy,
cycloalkyl, cycloalkylalkyl, (hydroxy)cycloalkylalkyl,
cycloalkylamino, cycloalkylaminoalkyl, (cycloalkylalkyl)amino,
(cycloalkyalkyl)aminoalkyl, cyanoalkyl, alkenyl, alkynyl, aryl,
aralkyl, aralkenyl, hydroxyalkyl, (hydroxy)aralkyl,
hydroxyalkylthioalkyl, hydroxyalkenyl, hydroxyalkynyl, alkoxyalkyl,
(alkoxy)aralkyl, aryloxyalkyl, aralkoxyalkyl, amino,
monoalkylamino, dialkylamino, monoarylamino, monoaralkylamino,
aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,
hydroxyalkylaminoalkyl, monoarylaminoalkyl, monoaralkylaminoalkyl,
alkylcarbonylamino, (alkylcarbonyl)(alkyl)amino,
alkylcarbonylaminoalkyl, (alkylcarbonyl)(alkyl)aminoalkyl,
alkoxycarbonylamino, (alkoxycarbonyl)(alkyl)amino,
alkoxycarbonylaminoalkyl, (alkoxycarbonyl)(alkyl)aminoalkyl,
carboxy, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,
alkylcarbonylalkyl, arylcarbonyl, arylcarbonylalkyl,
aralkylcarbonyl, aralkylcarbonylalkyl, carboxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
alkoxyalkylcarbonyloxyalkyl, aminocarbonyl, monoalkylaminocarbonyl,
dialkylaminocarbonyl, monoarylaminocarbonyl,
monoaralkylaminocarbonyl, aminocarbonylalkyl,
monoalkylaminocarbonylalkyl, dialkylaminocarbonylalky- l,
monoarylaminocarbonylalkyl, monoaralkylaminocarbonylalkyl, amidino,
guanidino, ureido, monoalkylureido, dialkylureido, ureidoalkyl,
monoalkylureidoalkyl, dialkylureidoalkyl, heterocyclyl and
heterocyclylalkyl;
[0012] R.sup.3 is a carbocylic ring system substituted by one or
more substituents independently selected from the group consisting
of hydrogen, hydroxy, hydroxysulfonyl, halo, alkyl, mercapto,
mercaptoalkyl, alkylthio, alkylsulfinyl, alkylsufonyl,
arylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl,
alkylsulfonylalkyl, alkoxy, hydroxyalkoxy, aryloxy, haloalkyl,
formyl, formylalkyl, nitro, nitroso, cyano, aralkoxy, haloalkoxy,
aminoalkoxy, cycloalkyl, cycloalkylalkyl, (hydroxy)cycloalkylalkyl,
cycloalkylamino, cycloalkylaminoalkyl, cyanoalkyl, alkenyl,
alkynyl, aryl, aralkyl, aralkenyl, hydroxyalkyl, (hydroxy)aralkyl,
(monoalkylamino)aralkyl, (hydroxyalkyl)hioalkyl, hydroxyalkenyl,
hydroxyalkynyl, alkoxyalkyl, (alkoxy)aralkyl, aryloxyalkyl,
aralkoxyalkyl, amino, monoalkylamino, dialkylamino, monoarylamino,
monoaralkylamino, aminoalkylamino, heterocyclylamino,
(cycloalkylalkyl)amino, alkylcarbonylamino, alkoxycarbonylamino,
alkenylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino,
heterocyclylcarbonylamino, haloalkylcarbonylamino,
alkoxyalkylcarbonylamino, alkoxycarbonylalkylcarbonylamino,
(alkylcarbonyl)(alkyl)amino, (alkoxycarbonyl)(alkyl)amino,
alkylsulfonylamino, aminoalkyl, monoalkylaminoalkyl,
dialkylaminoalkyl, hydroxyalkylaminoalkyl, monoarylaminoalkyl,
monoaralkylaminoalkyl, alkylcarbonylaminoalkyl,
arylcarbonylaminoalkyl, (alkylcarbonyl)(alkyl)am- inoalkyl,
(cycloalkyalkyl)aminoalkyl, alkoxycarbonylaminoalkyl,
alkoxycarbonylalkylcarbonylaminoalkyl,
(alkoxycarbonyl)(alkyl)aminoalkyl, alkylsulfonylaminoalkyl,
(alkylsulfonyl)(alkyl)aminoalkyl, arylsulfonylaminoalkyl,
(arylsulfonyl)(alkyl)aminoalkyl, heterocyclylaminoalkyl, carboxy,
alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, arylcarbonyl,
aralkylcarbonyl, (hydroxyalkoxy)carbonyl, carboxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
alkoxyalkylcarbonyloxyalkyl, dialkylaminocarbonyloxyalkyl,
alkylcarbonylalkyl, arylcarbonylalkyl, aralkylcarbonylalkyl,
aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl,
monoarylaminocarbonyl, monoaralkylaminocarbonyl,
(aminocarbonylalkyl)amin- ocarbonyl,
(monoalkylaminocarbonylalkyl)aminocarbonyl,
(carboxyalkyl)aminocarbonyl, (alkoxycarbonylalkyl)aminocarbonyl,
(aminoalkyl)aminocarbonyl, (hydroxyalkyl)aminocarbonyl,
aminocarbonylalkyl, monoalkylaminocarbonylalkyl,
dialkylaminocarbonylalky- l, monoarylaminocarbonylalkyl,
monoaralkylaminocarbonylalkyl, amidino, hydroxyamidino, guanidino,
ureido, monoalkylureido, monoarylureido, monoaralkylureido,
monohaloalkylureido, (monoalkyl)(monoaryl)ureido, dialkylureido,
diarylureido, (haloalkylcarbonyl)ureido, ureidoalkyl,
monoalkylureidoalkyl, dialkylureidoalkyl, monoarylureidoalkyl,
monoaralkylureidoalkyl, monohaloalkylureidoalkyl,
(haloalkyl)(alkyl)ureid- oalkyl, (alkoxycarbonylalkyl)ureidoalkyl,
glycinamido, monoalkylglycinamido, aminocarbonylglycinamido,
(alkoxyalkylcarbonyl)glyc- inamido,
(aminocarbonyl)(alkyl)glycinamido, (alkoxycarbonylalkylcarbonyl)(-
alkyl)glycinamido, (alkoxycarbonylaminoalkylcarbonyl)glycinamido,
arylcarbonylglycinamido, (arylcarbonyl)(alkyl)glycinamido,
(monoaralkylaminocarbonyl)glycinamido,
(monoaralkylaminocarbonyl)(alkyl)g- lycinamido,
(monoarylaminocarbonyl)glycinamido, (monoarylaminocarbonyl)(al-
kyl)glycinamido, glycinamidoalkyl, alaninamido,
monoalkylalaninamido, alaninamidoalkyl, heterocyclyl and
heterocyclylalkyl;
[0013] or R.sup.3 is a heterocyclic ring system substituted by one
or more substituents independently selected from the group
consisting of hydrogen, hydroxy, halo, alkyl, alkylsufonyl,
arylsulfonyl, alkoxy, hydroxyalkoxy, haloalkyl, formyl, nitro,
cyano, haloalkoxy, alkenyl, alkynyl, aryl, aralkyl, amino,
monoalkylamino, dialkylamino, monoarylamino, monoaralkylamino,
alkylcarbonylamino, alkoxycarbonylamino, alkenylcarbonylamino,
cycloalkylcarbonylamino, arylcarbonylamino, haloalkylcarbonylamino,
alkoxyalkylcarbonylamino, alkoxycarbonylalkylcarb- onylamino,
(alkylcarbonyl)(alkyl)amino, (alkoxycarbonyl)(alkyl)amino,
alkylsulfonylamino, aminoalkyl, monoalkylaminoalkyl,
dialkylaminoalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl,
(alkylcarbonyl)(alkyl)am- inoalkyl, alkoxycarbonylaminoalkyl,
carboxy, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,
arylcarbonyl, aralkylcarbonyl, aminocarbonyl,
monoalkylaminocarbonyl, dialkylaminocarbonyl,
monoarylaminocarbonyl, aminocarbonylalkyl,
monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl,
monoarylaminocarbonylalkyl, guanidino, ureido, monoalkylureido,
ureidoalkyl, monoalkylureidoalkyl, and glycinamido;
[0014] R.sup.4 is --O--, --N(R.sup.7)--, --C(R.sup.8).sub.2-- or a
bond;
[0015] R.sup.5 is an alkylene chain or an alkylidene chain, or, if
R.sup.4 is a bond, R.sup.5 is an alkylidene chain optionally
substituted by aryl or --N(R.sup.7).sub.2;
[0016] R.sup.6 is --C(O)-, --C(S)--, -CH.sub.2-- or a bond;
[0017] each R.sup.7 is independently selected from the group
consisting of hydrogen, alkyl, aryl, aralkyl, alkylcarbonyl,
alkylcarbonylalkyl, aralkylcarbonyl, aralkylcarbonylalkyl,
aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, and
alkoxycarbonyl; and
[0018] each R.sup.8 is independently selected from the group
consisting of hydrogen, alkyl, aryl, aralkyl, hydroxy, alkoxy,
hydroxyalkyl, alkoxyalkyl, amino, monoalkylamino, dialkylamino,
alkylcarbonylamino, cycloalkylcarbonylamino,
cycloalkylalkylcarbonylamino, alkoxycarbonylamino,
alkylsulfonylamino, arylcarbonylamino,
alkoxycarbonylalkylcarbonylamino, (alkylcarbonyl)(alkyl)amino,
aralkylcarbonylamino, (aralkylcarbonyl)(alkyl)amino,
alkylcarbonylaminoalkyl, cycloalkylcarbonylaminoalkyl,
alkoxycarbonylaminoalkyl, (alkylcarbonyl)(alkyl)aminoalkyl,
aralkylcarbonylaminoalkyl, heterocyclylcarbonylaminoalkyl,
(aralkylcarbonyl)(alkyl)aminoalkyl, arylsulfonylamino,
alkylsulfonylaminoalkyl, ureido, monoalkylureido,
monohaloalkylureido, dialkylureido, ureidoalkyl,
monoalkylureidoalkyl, dialkylureidoalkyl, monohaloalkylureidoalkyl,
aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl,
alkoxycarbonylalkyl, aminocarbonylalkyl,
monoalkylaminocarbonylalkyl, and dialkylaminocarbonylalkyl;
[0019] Y is a pharmaceutically acceptable counterion:
[0020] R.sup.1b is one or more substituents independently selected
from the group consisting of hydrogen, oxo, halo, alkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylaminoalkyl,
(cycloalkylalkyl)aminoalkyl, haloalkyl, alkenyl, alkynyl, aryl,
aralkyl, aralkenyl, formyl, formylalkyl, hydroxyalkyl,
hydroxyalkenyl, hydroxyalkynyl, (hydroxy)aralkyl,
(hydroxy)cycloalkylalkyl, mercaptoalkyl, cyanoalkyl,
haloalkylcarbonylaminoalkyl, (alkoxy)aralkyl, alkoxyalkyl,
aryloxyalkyl, aralkoxyalkyl, alkylthioalkyl, alkylsulfinylalkyl,
alkylsulfonylalkyl, hydroxyalkylthioalkyl, aminoalkyl,
monoalkylaminoalkyl, dialkylaminoalkyl, monoarylaminoalkyl,
monoaralkylaminoalkyl, alkylcarbonylaminoalkyl,
(alkylcarbonyl)(alkyl)aminoalkyl, azidoalkyl, ureidoalkyl,
monoalkylureidoalkyl, dialkylureidoalkyl,
(alkoxycarbonylalkyl)ureidoalkyl, alkoxycarbonylaminoalkyl,
hydroxyalkylaminoalkyl, aryloxyalkylcarbonyloxyalkyl,
alkoxyalkylcarbonyloxyalkyl, aralkoxyalkylcarbonyloxyalkyl,
alkylcarbonyl, alkylcarbonylalkyl, carboxy, alkoxycarbonyl,
aralkoxycarbonyl, aralkylcarbonyl, aminocarbonyl,
monoalkylaminocarbonyl, dialkylaminocarbonyl,
monoarylaminocarbonyl, monoaralkylaminocarbonyl, carboxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aminocarbonylalkyl,
monoalkylaminocarbonylalkyl, dialkylaminocarbonylalky- l,
monoarylaminocarbonylalkyl, monoaralkylaminocarbonylalkyl,
arylsulfonyl, heterocyclyl and heterocyclylalkyl; and
[0021] R.sup.9 is alkyl, aralkyl, haloalkyl, hydroxyalkyl,
alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, alkylcarbonylalkyl,
alkylcarbonylaminoalkyl, aminocarbonylalkyl,
monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl,
hetereocyclylalkyl, or cycloalkylalkyl;
[0022] R.sup.10 is a heterocyclyl optionally substituted by one or
more substituents selected from the group consisting of hydroxy,
mercapto, halo, alkyl, alkenyl, alkynyl, phenyl, phenylalkyl,
phenylalkenyl, alkoxy, phenoxy, phenylalkoxy, haloalkyl,
haloalkoxy, formyl, nitro, cyano, amidino, cycloalkyl,
hydroxyalkyl, alkoxyalkyl, phenoxyalkyl, phenylalkoxyalkyl, amino,
monoalkylamino, dialkylamino, monophenylamino,
monophenylalkylamino, aminoalkyl, monoalkylaminoalkyl,
dialkylaminoalkyl, monophenylaminoalkyl, monophenylalkylaminoalkyl,
carboxy, alkoxycarbonyl, phenylcarbonyl, benzylcarbonyl,
alkylcarbonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl,
monoalkylaminocarbonyl, dialkylaminocarbonyl, phenylaminocarbonyl,
aminocarbonylalkyl, monoalkylaminocarbonylalkyl,
dialkylaminocarbonylalkyl, ureido, monoalkylureido,
monophenylureido, and monobenzylureido;
[0023] provided that when R.sup.4 is --N(R.sup.7)--, R.sup.3 can
not be a heterocyclic ring system containing 4-8 members consisting
of carbon atoms and only one nitrogen atom.
[0024] Compounds of formulae Ia, Ib, Ic and Id are disclosed in
U.S. Pat. No. 6,207,665 and WO 98/56771 as being useful in treating
various inflammatory disorders including multiple sclerosis,
leukoencephalopathy, encephalomyelitis, Alzheimer's disease,
Guillian-Barre syndrome, acute cell-mediated renal transplant
rejection, allograft rejection, rheumatoid arthritis,
atherosclerosis, uricaria, angioderma, allergic conjunctivitis,
atopic dermatitis, allergic contact dermatitis, drug or insect
sting allergy or systemic anaphylaxis.
DETAILED DESCRIPTION OF THE INVENTION
[0025] We have discovered that compounds of formulae Ia, Ib, Ic and
Id are useful in treating myocarditis.
[0026] Definitions
[0027] As used in the specification and appended claims, unless
specified to the contrary, the following terms have the meaning
indicated:
[0028] "Alkyl" refers to a straight or branched chain monovalent or
divalent radical consisting solely of carbon and hydrogen,
containing no unsaturation and having from one to eight carbon
atoms, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl),
n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), n-heptyl, and the
like.
[0029] "Alkylcarbonyl" refer to a radical of the formula
--C(O)--R.sub.a where R.sub.a is an alkyl radical as defined above,
e.g., acetyl, ethylcarbonyl, n-propylcarbonyl, and the like.
[0030] "Alkylcarbonylalkyl" refers to a radical of the formula
--R.sub.a--C(O)--R.sub.a where each R.sub.a is independently an
alkyl radical as defined above, e.g., (acetyl)methyl,
2-(acetyl)ethyl, 4-(ethylcarbonyl)butyl, and the like.
[0031] "Alkylcarbonylamino" refers to a radical of the formula
--N(H)--C(O)--R.sub.a where R.sub.a is an alkyl radical as defined
above, e.g., acetylamino, ethylcarbonylamino,
n-propylcarbonylamino, and the like.
[0032] "(Alkylcarbonyl)(alkyl)amino" refers to a radical of the
formula --N(R.sub.a)--C(O)--R.sub.a where each R.sub.a is
independently an alkyl radical as defined above, e.g.,
N-methyl-N-acetylamino, N-ethyl-N-(ethylcarbonyl)amino, and the
like.
[0033] "Alkylcarbonylaminoalkyl" refers to a radical of the formula
--R.sub.a--N(H)C(O)--R.sub.a where each R.sub.a is independently an
alkyl radical as defined above, e.g., acetylaminomethyl,
2-(acetylamino)ethyl, 4-(ethylcarbonylamino)butyl, and the
like.
[0034] "(Alkylcarbonyl)(alkyl)aminoalkyl" refers to a radical of
the formula R.sub.a--N(R.sub.a)--C(O)--R.sub.a where each R.sub.a
is independently an alkyl radical as defined above, e.g.,
(N-methyl-N-acetylamino)methyl,
2-(N-ethyl--N-(ethylcarbonyl)amino)propyl- , and the like.
[0035] "Alkylthio" refers to a radical of the formula --S--R.sub.a
where R.sub.a is an alkyl radical as defined above, e.g.,
methylthio, ethylthio, n-propylthio, and the like.
[0036] "Alkylsulfinyl" refers to a radical of the formula
--S(O)R.sub.a where R.sub.a is an alkyl radical as defined above,
e.g., methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, and the
like.
[0037] "Alkylsulfonyl" refers to a radical of the formula
--S(O).sub.2R.sub.a where R.sub.a is an alkyl radical as defined
above, e.g., methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, and
the like.
[0038] "Alkylthioalkyl" refers to a radical of the formula
--R.sub.a--S--R.sub.a where each R.sub.a is independently an alkyl
radical as defined above, e.g., methylthiomethyl,
2-methylthioethyl, 2-ethylthiopropyl, and the like.
[0039] "Alkylsulfinylalkyl" refers to a radical of the formula
--R.sub.a--S(O)--R.sub.a where where each R.sub.a is independently
an alkyl radical as defined above, e.g., methylsulfinylmethyl,
2-methylsulfinylethyl, 2-ethylsulfinylpropyl, and the like.
[0040] "Alkylsulfonylalkyl" refers to a radical of the formula
--R.sub.a--S(O).sub.2--R.sub.a where each R.sub.a is independently
an alkyl radical as defined above, e.g., methylsulfonylmethyl,
2-methylsulfonylethyl, 2-ethylsulfonylpropyl, and the like.
[0041] "Alkylsulfonylamino" refers to a radical of the formula
--N(H)--S(O).sub.2--R.sub.a where R.sub.a is an alkyl radical as
defined above, e.g., methylsulfonylamino, ethylsulfonylamino,
iso-propylsulfonylamino, and the like.
[0042] "Alkylsulfonylaminoalkyl" refers to a radical of the formula
--R.sub.a--N(H)--S(O).sub.2--R.sub.a where each R.sub.a is
independently an alkyl radical as defined above, e.g.,
methylsulfonylaminomethyl, 2-(ethylsulfonylamino)ethyl,
3-(iso-propylsulfonylamino)propyl, and the like.
[0043] "(Alkylsulfonyl)(alkyl)aminoalkyl" refers to a radical of
the formula --R.sub.a--N(R.sub.a)--S(O).sub.2--R.sub.a where each
R.sub.a is independently an alkyl radical as defined above, e.g.,
(methylsulfonyl)(methyl)aminomethyl,
2-((ethylsulfonyl)(methyl)amino)ethy- l,
3-((iso-propylsulfonyl)(ethyl)amino)propyl, and the like.
[0044] "Alkenyl" refers to a straight or branched chain monovalent
or divalent radical consisting solely of carbon and hydrogen,
containing at least one double bond and having from two to eight
carbon atoms, e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl,
penta-1,4-dienyl, and the like.
[0045] "Alkenylcarbonylamino" refers to a radical of the formula
--N(H)--C(O)--R.sub.c where R.sub.c is an alkenyl radical as
defined above, e.g., ethenylcarbonylamino,
prop-2-enylcarbonylamino, but-2-enylcarbonylamino, and the
like.
[0046] "Alkynyl" refers to a straight or branched chain monovalent
or divalent radical consisting solely of carbon and hydrogen,
containing at least one triple bond and having from two to eight
carbon atoms, e.g., ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl,
pent-3-ynyl, and the like.
[0047] "Alkoxy" refers to a radical of the formula --OR.sub.a where
R.sub.a is an alkyl radical as defined above, e.g., methoxy,
ethoxy, n-propoxy, 1-methylethoxy (iso-propoxy), n-butoxy,
n-pentoxy, 1,1-dimethylethoxy (t-butoxy), and the like.
[0048] "Alkoxycarbonyl" refers to a radical of the formula
--C(O)OR.sub.a where R.sub.a is an alkyl radical as defined above,
e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, and the
like.
[0049] "Alkoxycarbonylalkyl" refers to a radical of the formula
--R.sub.a--C(O)OR.sub.a where each R.sub.a is independently an
alkyl radical as defined above, e.g., methoxycarbonylmethyl,
2-(ethoxycarbonyl)ethyl, 2-(methoxycarbonyl)propyl, and the
like.
[0050] "Alkoxyalkylcarbonyloxyalkyl" refers to a radical of the
formula --R.sub.a--OC(O)--R.sub.a--OR.sub.a where each R.sub.a is
independently an alkyl radical as defined above, e.g.,
methoxymethylcarbonyloxymethyl,
2-(2-(2-(ethoxy)ethylcarbonyloxy)ethyl)ethyl,
2-(3-(2-(ethoxy)ethylcarbon- yloxy)propyl)ethyl, and the like.
[0051] "Alkoxycarbonylamino" refers to a radical of the formula
--N(H)--C(O)--OR.sub.a where R.sub.a is an alkyl radical as defined
above, e.g., methoxycarbonylamino, ethoxycarbonylamino,
isopropoxycarbonylamino, and the like.
[0052] "(Alkoxycarbonyl)(alkyl)amino" refers to a radical of the
formula --N(R.sub.a)(C(O)OR.sub.a) where each R.sub.a is
independently an alkyl radical as defined above, e.g.,
N-methyl--N-methoxycarbonylamino, N-ethyl-N-ethoxycarbonylamino,
and the like.
[0053] "Alkoxycarbonylaminoalkyl" refers to a radical of the
formula --R.sub.a--N(H)--C(O)--OR.sub.a where each R.sub.a is
independently an alkyl radical as defined above, e.g.,
methoxycarbonylaminomethyl, 2-(ethoxycarbonylamino)ethyl,
isopropoxycarbonylaminomethyl, and the like.
[0054] "(Alkoxycarbonyl)(alkyl)aminoalkyl" refers to a radical of
the formula --R.sub.a--N(R.sub.a)(C(O)OR.sub.a) where each R.sub.a
is independently an alkyl radical as defined above, e.g.,
N-methyl-N-methoxycarbonylaminomethyl,
2-(N-ethyl-N-ethoxycarbonylamino)e- thyl, and the like.
[0055] "(Alkoxy)aralkyl" refers to an aralkyl radical wherein the
alkyl group therein is substituted by an alkoxy radical as defined
above, e.g., 2-phenyl-1-methoxyethyl, phenyl(methoxy)methyl, and
the like.
[0056] "Alkoxyalkylcarbonylamino" refers to a radical of the
formula --N(H)--C(O)--R.sub.a--O--R.sub.a where each R.sub.a is an
alkyl radical as defined above, e.g., methoxymethylcarbonylamino,
ethoxyethylcarbonylamino, methoxyethylcarbonylamino, and the
like.
[0057] "Alkoxycarbonylalkylcarbonylamino" refers to a radical of
the formula --N(H)--C(O)--R.sub.a--C(O)OR.sub.a where each R.sub.a
is independently an alkyl radical as defined above, e.g.,
ethoxycarbonylmethylcarbonylamino,
methoxycarbonylmethylcarbonylamino,
(2-ethoxycarbonylethyl)carbonylamino,
(2-methoxycarbonylethyl)carbonylami- no, and the like.
[0058] "Alkoxycarbonylalkylcarbonylaminoalkyl" refers to a radical
of the formula --R.sub.a--N(H)--C(O)--R.sub.a--C(O)OR.sub.a where
each R.sub.a is independently an alkyl radical as defined above,
e.g., ethoxycarbonylmethylcarbonylaminomethyl,
2-(methoxycarbonylmethylcarbonyl- amino)ethyl,
1-((2-ethoxycarbonylethyl)carbonylamino)ethyl,
(2-methoxycarbonylethyl)carbonylaminomethyl, and the like.
[0059] "(Alkoxycarbonylalkyl)aminocarbonyl" refers to a radical of
the formula --C(O)--N(H)--R.sub.a--C(O)--OR.sub.a where each
R.sub.a is independently an alkyl radical as defined above, e.g.,
(methoxycarbonylmethyl)aminocarbonyl,
(2-(ethoxycarbonyl)ethyl)aminocarbo- nyl,
(1-(methoxycarbonyl)ethyl)aminocarbonyl, and the like.
[0060] "(Alkoxycarbonylalkyl)ureidoalkyl" refers to a radical of
the formula --R.sub.a--N(H)--C(O)--N(H)--R.sub.a--C(O)--OR.sub.a
where each R.sub.a is independently an alkyl radical as defined
above and where the nitrogen to which --R.sub.a--C(O)--OR.sub.a is
attached is indicated as "N", e.g.,
(ethoxycarbonylmethyl)ureidomethyl, (2-(ethoxycarbonyl)ethyl)u-
reidomethyl, 2-((2-(ethoxycarbonyl)ethyl)ureido)ethyl, and the
like.
[0061] "(Alkoxycarbonylalkylcarbonyl)(alkyl)glycinamido" refers to
a radical of the formula
--N(H)--C(O)--CH.sub.2--N(R.sub.a)--C(O)--R.sub.a-- -C(O)--OR.sub.a
where each R.sub.a is independently an alkyl radical as defined
above, e.g., (methoxycarbonylmethylcarbonyl)(methyl)glycinamido,
((2-ethoxycarbonylethyl)carbonyl)(ethyl)glycinamido, and the
like.
[0062] "(Alkoxyalkylcarbonyl)glycinamido" refers to a radical of
the formula --N(H)--C(O)--CH.sub.2--N(H)--C(O)--R.sub.a--O--R.sub.a
where each R.sub.a is independently an alkyl radical as defined
above, e.g., (methoxyacetyl)glycinamido, (ethoxyacetyl)glycinamido,
and the like.
[0063] "Alkylene chain" refers to straight or branched chain
divalent radical consisting solely of carbonyl and hydrogen,
containing no unsaturation and having from one to eight carbon
atoms, e.g., methylene, ethylene, propylene, n-butylene, and the
like.
[0064] "Alkylidene chain" refers to a straight or branched chain
unsaturated divalent radical consisting solely of carbon and
hydrogen atoms, having from one to eight carbon atoms, wherein the
unsaturation is present only as double bonds and wherein a double
bond can exist between the first carbon of the chain and the rest
of the molecule, e.g., ethylidene, propylidene, n-butylidene, and
the like.
[0065] "Amino" refers to the radical --NH.sub.2.
[0066] "Aminoalkyl" refers to a radical of the formula
--R.sub.aNH.sub.2 where R.sub.a is an alkyl radical as defined
above, e.g., aminomethyl, 2-aminoethyl, 3-aminopropyl,
2-aminopropyl, and the like.
[0067] "Aminoalkylamino" refers to a radical of the formula
--N(H)--R.sub.a--NH.sub.2 where R.sub.a is an alkyl radical as
defined above, e.g., aminomethylamino, (2-aminoethyl)amino,
(2-aminopropyl)amino, and the like.
[0068] "Aminoalkoxy" refers to a radical of a formula
--OR.sub.a--NH.sub.2 where R.sub.a is an alkyl radical as defined
above, e.g., aminomethoxy, 2-aminoethoxy, 3-aminopropoxy,
2-aminopropoxy, 4-aminobutoxy, and the like.
[0069] "Aminocarbonyl" refers to the radical --C(O)NH.sub.2.
[0070] "Aminocarbonylglycinamido" refers to a radical of the
formula --N(H)--C(O)--CH.sub.2--N(H)--C(O)--NH.sub.2.
[0071] "(Aminocarbonyl)(alkyl)glycinamido" refers to a radical of
the formula --N(H)--C(O)--CH.sub.2--N(R.sub.a)--C(O)--NH.sub.2
where R.sub.a is an alkyl radical as defined above and where the
nitrogen with the R.sub.a substituent is designated as "N", e.g.,
(aminocarbonyl)(N'-methyl- )glycinamido,
(aminocarbonyl)(N'-ethyl)glycinamido, and the like.
[0072] "Aminocarbonylalkyl" refers to a radical of the formula
--R.sub.a--C(O)NH.sub.2 where R.sub.a is an alkyl radical as
defined above, e.g., aminocarbonylmethyl, 2-(aminocarbonyl)ethyl,
2-(aminocarbonyl)propyl, and the like.
[0073] "(Aminocarbonylalkyl)aminocarbonyl" refers to a radical of
the formula --C(O)--N(H)--R.sub.a--C(O)--NH.sub.2 where R.sub.a is
an alkyl radical as defined above, e.g.,
(aminocarbonylmethyl)aminocarbonyl,
(2-aminocarbonylethyl)aminocarbonyl,
(1-aminocarbonylethyl)aminocarbonyl, and the like.
[0074] "(Aminoalkyl)aminocarbonyl" refers to a radical of the
formula --C(O)--N(H)--R.sub.a--NH.sub.2 where R.sub.a is an alkyl
radical as defined above, e.g., (aminomethyl)aminocarbonyl,
(2-aminoethyl)aminocarbo- nyl, (1-aminoethyl)aminocarbonyl, and the
like.
[0075] "Amidino" refers to the radical --C(NH)NH.sub.2.
[0076] "Aryl" refers to a phenyl or naphthyl radical. Unless stated
otherwise specifically in the specification, the term "aryl" or the
prefix "ar-" (such as in "aralkyl") is meant to include aryl
radicals optionally substituted by one or more substituents
selected from the group consisting of hydroxy, mercapto, halo,
alkyl, alkenyl, alkynyl, phenyl, phenylalkyl, phenylalkenyl,
alkoxy, phenoxy, phenylalkoxy, haloalkyl, haloalkoxy, formyl,
nitro, cyano, amidino, cycloalkyl, hydroxyalkyl, alkoxyalkyl,
phenoxyalkyl, phenylalkoxyalkyl, amino, monoalkylamino,
dialkylamino, monophenylamino, monophenylalkylamino, aminoalkyl,
monoalkylaminoalkyl, dialkylaminoalkyl, monophenylaminoalkyl,
monophenylalkylaminoalkyl, alkylcarbonyl, carboxy, alkoxycarbonyl,
carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl,
monoalkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl,
monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, as defined
herein.
[0077] "Arylcarbonyl" refers to a radical of the formula
--C(O)R.sub.b where R.sub.b is an aryl radical as defined above,
e.g., phenylcarbonyl and naphthalen-2-ylcarbonyl, and the like.
[0078] "Arylcarbonylalkyl" refers to a radical of the formula
--R.sub.aC(O)R.sub.b where R.sub.a is an alkyl radical as defined
above and R.sub.b is an aryl radical as defined above, e.g.,
phenylcarbonylmethyl, 2-(phenylcarbonyl)ethyl,
3-(naphthalen-2-ylcarbonyl- )propyl, and the like.
[0079] "Arylcarbonylaminoalkyl" refers to a radical of the formula
--R.sub.a--N(H)--C(O)--R.sub.b where R.sub.a is an alkyl radical as
defined above and R.sub.b is an aryl radical as defined above,
e.g., (4-methoxyphenyl)carbonylaminomethyl,
2-((4-fluorophenyl)carbonylamino)et- hyl,
1-((4-chlorophenyl)carbonylamino)ethyl, and the like.
[0080] "Arylsulfonyl" refers to a radical of the formula
--S(O).sub.2--R.sub.b where R.sub.b is an aryl radical as defined
above, e.g., phenylsulfonyl, (4-chlorophenyl)sulfonyl,
(3-nitrophenyl)sulfonyl, and the like.
[0081] "Arylsulfonylamino" refers to a radical of the formula
--N(H)--S(O).sub.2--R.sub.b where R.sub.b is an aryl radical as
defined above, e.g., phenylsulfonylamino,
(4-chlorophenyl)sulfonylamino, (4-fluorophenyl)sulfonylamino,
(3-nitrophenyl)sulfonylamino), and the like.
[0082] "Arylsulfonylaminoalkyl" refers to a radical of the formula
--R.sub.a--N(H)--S(O).sub.2--R.sub.b where R.sub.a is an alkyl
radical as defined above and R.sub.b is an aryl radical as defined
above, e.g., phenylsulfonylaminomethyl,
(4-chlorophenyl)sulfonylaminomethyl,
2-((4-fluorophenyl)sulfonylamino)ethyl,
1-((3-nitrophenyl)sulfonylamino)e- thyl, and the like.
[0083] "(Arylsulfonyl)(alkyl)aminoalkyl" refers to a radical of the
formula --R.sub.a--N(R.sub.a)--S(O).sub.2--R.sub.b where each
R.sub.a is independently an alkyl radical as defined above and
R.sub.b is an aryl radical as defined above, e.g.,
(phenylsulfonyl)(methyl)aminomethyl,
((4-chlorophenyl)sulfonyl)(ethyl)aminomethyl,
2-(((4-fluorophenyl)sulfony- l)(methyl)amino)ethyl,
1-(((3-nitrophenyl)sulfonyl)(ethyl)amino)ethyl, and the like.
[0084] "(Alkoxycarbonylaminoalkylcarbonyl)glycinamido" refers to a
radical of the formula
--N(H)--C(O)--CH.sub.2--N(H)--C(O)--N(H)--C(O)--OR.sub.a where
R.sub.a is an alkyl radical as defined above, e.g.,
(ethoxycarbonylaminocarbonyl)glycinamido,
(methoxycarbonylaminocarbonyl)g- lycinamido, and the like.
[0085] "Arylcarbonylglycinamido" refers to a radical of the formula
--N(H)--C(O)--CH.sub.2--N(H)--C(O)--R.sub.b where R.sub.b is an
aryl radical as defined above, e.g., phenylcarbonylglycinamido,
(4-fluoro-3-trifluoromethylphenyl)carbonylglycinamido,
(4-fluorophenyl)carbonylglycinamido, and the like.
[0086] "(Arylcarbonyl)(alkyl)glycinamido" refers to a radical of
the formula --N(H)--C(O)--CH.sub.2--N(R.sub.a)--C(O)--R.sub.b where
R.sub.a is an alkyl radical as defined above and R.sub.b is an aryl
radical as defined above and the nitrogen to which the R.sub.a
radical is attached is designated as "N", e.g.,
(phenylcarbonyl)(N'-methyl)glycinamido,
((4-fluoro-3-trifluoromethylphenyl)carbonyl)(N'-ethyl)glycinamido,
((4-fluorophenyl)carbonyl)(N'-methyl)glycinamido, and the like.
[0087] "Aralkyl" refers to a radical of the formula
--R.sub.aR.sub.b where R.sub.a is an alkyl radical as defined above
and R.sub.b is an aryl radical as defined above, e.g., benzyl, and
the like.
[0088] "Aralkylcarbonyl" refers to a radical of the formula
--C(O)--R.sub.d where R.sub.d is an aralkyl radical as defined
above, e.g., benzylcarbonyl, 1-(phenyl)ethylcarbonyl, and the
like.
[0089] "Aralkylcarbonylalkyl" refers to a radical of the formula
--R.sub.aC(O)R.sub.d where R.sub.a is an alkyl radical as defined
above and R.sub.d is an aralkyl radical as defined above, e.g.,
benzylcarbonylmethyl, 2-(1-(phenyl)ethylcarbonyl)ethyl, and the
like.
[0090] "Aralkenyl" refers to a radical of the formula
--R.sub.cR.sub.b where R.sub.b is an aryl radical as defined above
and R.sub.c is an alkenyl radical as defined above, e.g.,
3-phenylpropylid-1-enyl, and the like.
[0091] "Aryloxy" refers to a radical of the formula --OR.sub.b
where R.sub.b is an aryl radical as defined above, e.g., phenoxy
and naphthoxy, and the like.
[0092] "Aralkoxycarbonyl" refers to a radical of the formula
--C(O)OR.sub.d where R.sub.d is an aralkyl radical as defined
above, e.g., benzyloxycarbonyl, and the like.
[0093] "Aralkoxycarbonylalkyl" refers to a radical of the formula
--R.sub.aC(O)OR.sub.d where R.sub.a is an alkyl radical as defined
above and R.sub.d is an aralkyl radical as defined above, e.g.,
benzyloxycarbonylmethyl, 2-(benzyloxycarbonyl)ethyl,
3-((naphthalen-2-yl)oxy)carbonyl)propyl, and the like.
[0094] "Aryloxyalkyl" refers to a radical of the formula
--R.sub.a--OR.sub.b where R.sub.a is an alkyl radical as defined
above and R.sub.b is an aryl radical as defined above, e.g.,
phenoxymethyl, 2-(phenoxy)ethyl, 3-(phenoxy)propyl, and the
like.
[0095] "Aryloxyalkylcarbonyloxyalkyl" refers to a radical of the
formula --R.sub.a--OC(O)--R.sub.a--OR.sub.b where each R.sub.a is
independently an alkyl radical as defined above and R.sub.b is an
aryl radical as defined above, e.g.,
phenoxymethylcarbonyloxymethyl, (2-phenoxyethyl)carbonyloxymethyl,
3-((2-phenoxyethyl)carbonyloxy)propyl, and the like.
[0096] "Aralkoxy" refers to a radical of the formula --OR.sub.d
where R.sub.d is an aralkyl radical as defined above, e.g.,
benzyloxy, and the like.
[0097] "Aralkoxylalkyl" refers to a radical of the formula
--R.sub.a--OR.sub.d where R.sub.a is an alkyl radical as defined
above and R.sub.d is an aralkyl radical as defined above, e.g.,
benzyloxymethyl, 2-phenylethoxymethyl, and the like.
[0098] "Aralkoxyalkylcarbonyloxyalkyl" refers to a radical of the
formula --R.sub.a--OC(O)--R.sub.a--OR.sub.d where each R.sub.a is
independently an alkyl radical as defined above and R.sub.d is an
aralkyl radical as defined above, e.g.,
benzyloxymethylcarbonyloxymethyl,
(2-(phenyl)ethoxymethyl)-carbonyloxymethyl,
2-((2-(phenyl)ethoxymethyl)ca- rbonyloxy)ethyl, and the like.
[0099] "Alkoxyalkyl" refers to a radical of the formula
--R.sub.aOR.sub.a where each R.sub.a is independently an alkyl
radical as defined above, e.g., methoxyethyl, ethoxymethyl,
propoxymethyl, propoxyethyl, and the like.
[0100] "Alaninamido" refers to a radical of the formula
--N(H)--C(O)--C(CH.sub.3)H--NH.sub.2.
[0101] "Alanimamidoalkyl" refers to a radical of the formula
--R.sub.a--N(H)--C(O)--C(CH.sub.3)H--NH.sub.2 where R.sub.a is an
alkyl radical as defined above, e.g., alaninamidomethyl,
2-(alaninamido)ethyl, 1-(alaninamido)ethyl, 3-(alaninamido)propyl,
and the like.
[0102] "Azidoalkyl" refers to radical of the formula
--R.sub.a--N.sub.3 where R.sub.a is an alkyl radical as defined
above, e.g., 2-azidoethyl, 3-azidopropyl, 2-azidopropyl,
4-azidobutyl, and the like.
[0103] "Benzyl" refers to a radical of the formula
--CH.sub.2--R.sub.h where R.sub.h is a phenyl radical optionally
substituted by one or more substituents selected from the group
consisting of hydroxy, halo, alkyl, haloalkyl, alkoxy, alkenyl,
nitro, cyano, amino, monoalkylamino, dialkylamino, alkylcarbonyl,
carboxy, alkoxycarbonyl, and aminocarbonyl.
[0104] "Benzylcarbonyl" refers to a radical of the formula
--C(O)--CH.sub.2--R.sub.h where R.sub.h is a phenyl radical as
defined above, e.g., (4-methoxybenzyl)carbonyl,
(3-fluorobenzyl)carbonyl, and the like.
[0105] "Carboxy" refers to the radical --C(O)OH.
[0106] "Carboxyalkyl" refers to the radical of the formula
--R.sub.a--C(O)OH where R.sub.a is an alkyl radical as defined
above, e.g., carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, and
the like.
[0107] "(Carboxyalkyl)aminocarbonyl" refers to a radical of the
formula --C(O)--N(H)--R.sub.a--C(O)OH where R.sub.a is an alkyl
radical as defined above, e.g., (carboxymethyl)am inocarbonyl,
(2-carboxyethyl)am inocarbonyl, ( 1-carboxyethyl)aminocarbonyl, and
the like.
[0108] "Carbocyclic ring system" refers to a stable 3- to
15-membered ring radical consisting solely of carbon and hydrogen
atoms. For purposes of this invention, the carbocyclic ring system
radical may be a monocyclic, bicyclic or tricyclic ring system, and
may include fused or bridged ring systems, and the ring system may
be partially or fully saturated or aromatic, and the carbon atoms
in the ring system may be optionally oxidized. Examples of such
carbocyclic ring system radicals include, but are not limited to,
cyclopropyl, cyclobutyl, cyclohexyl, norbornane, norbornene,
adamantyl, bicyclo[2.2.2]octane, phenyl, naphthyl, indenyl,
azulenyl, fluorenyl, anthracenyl, and the like.
[0109] "Cycloalkyl" refers to a stable 3- to 10-membered monocyclic
or bicyclic radical which is saturated, and which consist solely of
carbon and hydrogen atoms, e.g., cyclopropyl, cyclobutyl,
cyclobutyl, cyclohexyl, decalinyl and the like. Unless otherwise
stated specifically in the specification, the term "cycloalkyl" is
meant to include cycloalkyl radicals which are optionally
substituted by one or more substituents independently selected from
the group consisting of alkyl, halo, hydroxy, amino, nitro, alkoxy,
carboxy, phenyl and alkoxycarbonyl.
[0110] "Cycloalkylalkyl" refers to a radical of the formula
--R.sub.a--R.sub.e where R.sub.a is an alkyl radical as defined
above and R.sub.e is a cycloalkyl radical as defined above, e.g.,
cyclopropylmethyl, 2-cyclobutylethyl, 3-cyclohexylpropyl, and the
like.
[0111] "Cycloalkylamino" refers to a radical of the formula
--N(H)--R.sub.e where R.sub.e is a cycloalkyl radical as defined
above, e.g., cyclopropylamino, cyclobutylamino, cyclohexylamino,
and the like.
[0112] "Cycloalkylaminoalkyl" refers to a radical of the formula
--R.sub.a--N(H)--R.sub.e where R.sub.a is an alkyl radical as
defined above and R.sub.e is a cycloalkyl radical as defined above,
e.g., cyclopropylaminomethyl, 2-(cyclobutylamino)ethyl,
cyclohexylaminomethyl, and the like.
[0113] "(Cycloalkylalkyl)amino" refers to a radical of the formula
--N(H)--R.sub.a--R.sub.e where R.sub.a is an alkyl radical as
defined above and R.sub.e is a cycloalkyl radical as defined above,
e.g., (cyclopropylmethyl)amino, (2-cyclobutylethyl)amino,
(3-cyclohexylpropyl)amino, and the like.
[0114] "(Cycloalkylalkyl)aminoalkyl" refers to a radical of the
formula --R.sub.a--N(H)--R.sub.a--R.sub.e where each R.sub.a is
independently an alkyl radical as defined above and R.sub.e is a
cycloalkyl radical as defined above, e.g.,
(cyclopropylmethyl)aminomethyl, 2-((2-cyclobutylethyl)amino)ethyl,
(3-cyclohexylpropyl)am inomethyl, and the like.
[0115] "Cycloalkylcarbonylamino" refers to a radical of the formula
--C(O)--N(H)--R.sub.e where R.sub.e is a cycloalkyl radical as
defined above, e.g., cyclopropylcarbonylamino,
(2-phenylcyclopropyl)carbonylamino- , cyclohexylcarbonylamino,
4-cyanodecalinylcarbonylamino, cyclopentylcarbonylamino, and the
like.
[0116] "Cycloalkylcarbonylaminoalkyl" refers to a radical of the
formula --R.sub.a--C(O)--N(H)--R.sub.e where R.sub.a is an alkyl
radical as defined above and R.sub.e is a cycloalkyl radical as
defined above, e.g., cyclopropylcarbonylaminomethyl,
2-((2-phenylcyclopropyl)carbonylamino)eth- yl,
1-(cyclohexylcarbonylamino)ethyl,
(3-phenylcyclopentyl)carbonylaminome- thyl, and the like.
[0117] "Cycloalkylalkylcarbonylamino" refers to a radical of the
formula --C(O)--N(H)--R.sub.a--R.sub.e where R.sub.a is an alkyl
radical as defined above and R.sub.e is a cycloalkyl radical as
defined above, e.g., (cyclopropylmethyl)carbonylamino,
((2-phenylcyclopropyl)methyl)carbonylam- ino,
(2-cyclohexylethyl)carbonylamino, (1-cyclohexylethyl)carbonylamino,
and the like.
[0118] "Cyano" refers to the radical --CN.
[0119] "Cyanoalkyl" refers to a radical of the formula --R.sub.aCN
where R.sub.a is an alkyl radical as defined above, cyanomethyl,
2-(cyano)ethyl, 3-(cyano)propyl, and the like.
[0120] "DMF" refers to N,N-dimethylformamide.
[0121] "DMSO" refers to dimethylsulfoxide.
[0122] "Dialkylamino" refers to a radical of the formula
--N(R.sub.a)R.sub.a where each R.sub.a is independently an alkyl
radical as defined above, e.g., dimethylamino, methylethylamino,
diethylamino, dipropylamino, ethylpropylamino, and the like.
[0123] "Dialkylaminoalkyl" refers to a radical of the formula
--R.sub.a--N(R.sub.a)R.sub.a where each R.sub.a is independently an
alkyl radical as defined above, e.g., dimethylaminomethyl,
methyethylaminomethyl, 2-diethylaminoethyl, 3-dipropylaminopropyl,
and the like.
[0124] "Dialkylaminocarbonyl" refers to a radical of the formula
--C(O)N(R.sub.a)R.sub.a where each R.sub.a is independently an
alkyl radical as defined above, e.g., d imethylaminocarbonyl,
methylethylaminocarbonyl, diethylaminocarbonyl,
dipropylaminocarbonyl, ethylpropylaminocarbonyl, and the like.
[0125] "Dialkylaminocarbonylalkyl" refers to a radical of the
formula --R.sub.a--C(O)N(R.sub.a)R.sub.a where each R.sub.a is
independently an alkyl radical as defined above, e.g.,
dimethylaminocarbonylmethyl, 2-(methylethylaminocarbonyl)ethyl,
3-(diethylaminocarbonyl)propyl, 2-(dipropylaminocarbonyl)propyl,
and the like.
[0126] "Dialkylaminocarbonyloxyalkyl" refers to a radical of the
formula --R.sub.a--O--C(O)-- N(R.sub.a)R.sub.a where each R.sub.a
is independently an alkyl radical as defined above, e.g,
dimethylaminocarbonyloxymethyl,
2-(methylethylaminocarbonyloxy)ethyl,
3-(diethylaminocarbonyloxy)propyl,
2-(dipropylaminocarbonyloxy)propyl, and the like.
[0127] "Dialkylureido" refers to a radical of the formula
--N(H)--C(O)--N(R.sub.a)(R.sub.a) or a radical of the formula
--N(R.sub.a)--C(O)--N(R.sub.a)H where each R.sub.a is independently
an alkyl radical as defined above and the attaching nitrogen is
designated as "N" and the other nitrogen is designated as "N",
e.g., N',N'-di(methyl)ureido, N'-methyl-N'-ethylureido,
N',N'-di(ethyl)ureido, N',N'-di(propyl)ureido,
N-methyl-N'-ethylureido, and the like.
[0128] "Diarylureido" refers to a radical of the formula
--N(H)--C(O)--N(R.sub.b)(R.sub.b) or a radical of the formula
--N(R.sub.b)--C(O)--N(R.sub.b)H where each R.sub.b is independently
an aryl radical as defined above and the attaching nitrogen is
designated as "N" and the other nitrogen is designated as "N",
e.g., N',N'-di(phenyl)ureido, N'-phenyl-N'-(3-nitro)phenylureido,
N',N'-di(4-methoxyphenyl)ureido, N',N'-di(4-chlorophenyl)ureido,
N4-chlorophenyl-N'-(3-chlorophenyl)ureido and the like.
[0129] "Dialkylureidoalkyl" refers to a radical of the formula
--R.sub.a--N(H)--C(O)--N(R.sub.a)(R.sub.a) or a radical of the
formula --R.sub.a--N(R.sub.a)--C(O)--N(R.sub.a)H where each R.sub.a
is independently an alkyl radical as defined above and the attached
nitrogen is designated as "N" and the other nitrogen is designated
as "N", e.g., N',N'-di(methyl)ureidomethyl,
2-(N'-methyl-N'-ethylureido)ethyl, 1-(N', N'-di(ethyl)ureido)ethyl,
3-(N',N'-di(propyl)ureido)propyl, 2-(N-methyl-N'-ethylureido)ethyl,
and the like.
[0130] "Formyl" refers to the radical --C(O)H.
[0131] "Formylalkyl" refers to a radical --R.sub.a--C(O)H where
R.sub.a is an alkyl radical as defined above, e.g., formylmethyl,
2-(formyl)ethyl, 3-(formyl)propyl, and the like.
[0132] "Glycinamido" refers to a radical of the formula
--N(H)--C(O)--CH.sub.2--NH.sub.2.
[0133] "Glycinamidoalkyl" refers to a radical of the formula
--R.sub.a--N(H)--C(O)--CH.sub.2--NH.sub.2 where R.sub.a is an alkyl
radical as defined above, e.g., glycinamidomethyl,
2-(glycinamido)ethyl, 1-(glycinamido)ethyl, 3-(glycinamido)propyl,
and the like.
[0134] "Guanidino" refers to the radical
--N(H)--C(NH)--NH.sub.2.
[0135] "Halo" refers to bromo, chloro, iodo or fluoro.
[0136] "Haloalkyl" refers to an alkyl radical, as defined above,
that is substituted by one or more halo radicals, as defined above,
e.g., trifluoromethyl, difluoromethyl, trichloromethyl,
2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl,
3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the
like.
[0137] "Haloalkoxy" refers to a radical of the formula --OR.sub.f
where R.sub.f is an haloalkyl radical as defined above, e.g.,
trifluoromethoxy, difluoromethoxy, trichloromethoxy,
2,2,2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy,
3-bromo-2-fluoropropoxy, 1-bromomethyl-2-bromoethoxy, and the
like.
[0138] "Haloalkylcarbonylamino" refers to a radical of the formula
--N(H)--C(O)--R.sub.f where R.sub.f is an haloalkyl radical as
defined above, e.g., trifluoromethylcarbonylamino,
trifluoromethylcarbonylamino, 2-bromoethylcarbonylamino, and the
like.
[0139] "(Haloalkylcarbonyl)ureido" refers to a radical of the
formula --N(H)--C(O)--N(H)--C(O)--R.sub.f where R.sub.f is a
haloalkyl radical as defined above, e.g.,
(trichloromethylcarbonyl)ureido, (3-fluoropropylcarbonyl)ureido,
and the like.
[0140] "(Haloalkyl)(alkyl)ureidoalkyl" refers to a radical of the
formula --R.sub.a--N(R.sub.a)--C(O)--N(H)--R.sub.f or a a radical
of the formula --R.sub.a--N(R.sub.f)--C(O)--N(H)--R.sub.a or a
radical of the formula --R.sub.a--N(H)--C(O)--N(R.sub.a)R.sub.f
where each R.sub.a is independently an alkyl radical as defined
above and R.sub.f is an haloalkyl radical as defined above and
terminal nitrogen is designated as "N" and the other nitrogen is
designated as "N", e.g., N'-(2-chloroethyl)-N-(methyl)ureidomethyl,
and 2-(N'-(2-chloroethyl)-N-(m- ethyl)ureido)ethyl, and the
like.
[0141] "Haloalkylcarbonylaminoalkyl" refers to a radical of the
formula --R.sub.a--N(H)--C(O)--R.sub.f where R.sub.a is an alkyl
radical as defined above and R.sub.f is an haloalkyl radical as
defined above, e.g., trifluoromethylcarbonylaminomethyl,
2-(trifluoromethylcarbonylamino)ethyl- , and the like.
[0142] "Hydroxy" refers to the radical --OH.
[0143] "Hydroxyalkyl" refers to a alkyl radical as defined above
that is substituted by a hydroxy radical, e.g., hydroxymethyl,
2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl,
3-hydroxybutyl, and the like.
[0144] "(Hydroxyalkyl)aminocarbonyl" refers to a radical of the
formula --C(O)--N(H)--R.sub.a--OH where R.sub.a is an alkyl radical
as defined above, e.g., hydroxymethylaminocarbonyl,
(2-hydroxyethyl)aminocarbonyl, (1-hydroxyethyl)aminocarbonyl, and
the like.
[0145] "Hydroxyalkoxy" refers to a radical of the formula
--OR.sub.a--OH where R.sub.a is an alkyl radical as defined above,
e.g., 2-hydroxyethoxy, 2-hydroxypropoxy, 4-hydroxybutoxy,
3-hydroxybutoxy, and the like.
[0146] "(Hydroxyalkoxy)carbonyl" refers to a radical of the formula
--C(O)--OR.sub.a--OH where R.sub.a is an alkyl radical as defined
above, e.g., (2-hydroxyethoxy)carbonyl, (2-hydroxypropoxy)carbonyl,
(4-hydroxybutoxy)carbonyl, (3-hydroxybutoxy)carbonyl, and the
like.
[0147] "(Hydroxy)aralkyl" refers to an aralkyl radical as defined
above wherein the alkyl radical therein is substituted by a hydroxy
radical, e.g., (phenyl)(hydroxy)methyl, 2-phenyl-1-hydroxyethyl,
2-phenyl-3-hydroxypropyl, and the like.
[0148] "(Hydroxyalkylthio)alkyl" refers to an alkylthioalkyl
radical as defined above that is substituted by an hydroxy radical,
e.g., 2-hydroxyethylthiomethyl, 2-(hydroxymethylthio)ethyl, and the
like.
[0149] "Hydroxyalkenyl" refers to an alkenyl radical as defined
above that is substituted by a hydroxy radical, e.g.,
3-hydroxyprop-1-enyl, 4-hydroxybut-1-enyl, 4-hydroxypent-1-enyl,
5-hydroxypenta-1,3-dienyl, and the like.
[0150] "Hydroxyalkynyl" refers to an alkynyl radical as defined
above that is substituted by a hydroxy radical, e.g.,
3-hydroxyprop-ynyl, 4-hydroxypent-2-ynyl, 1-hydroxybut-3-ynyl, and
the like.
[0151] "(Hydroxy)cycloalkylalkyl" refers to a radical of the
formula --R.sub.a(OH)--R.sub.e where R.sub.a is an alkyl radical as
defined above and R.sub.e is a cycloalkyl radical as defined above
and where the OH radical is a substituent on any carbon of the
R.sub.a radical, e.g., 2-cyclopropyl-1-hydroxyethyl,
(4-hydroxycyclohexyl)methyl, and the like.
[0152] "Hydroxyalkylaminoalkyl" refers to a monoalkylaminoalkyl
radical as defined below that is substituted by a hydroxy radical,
e.g., 2-hydroxyethylaminomethyl, 2-(3-hydroxypropylamino)ethyl, and
the like.
[0153] "Hydroxyamidino" refers to a radical of the formula
--C(NH.sub.2).dbd.NOH.
[0154] "Heterocyclic ring system" refers to a stable 3- to
15-membered ring radical which consists of carbon atoms and from
one to five heteroatoms selected from the group consisting of
nitrogen, oxygen and sulfur. For purposes of this invention, the
heterocyclic ring system radical may be a monocyclic, bicyclic or
tricyclic ring system, which may include fused or bridged ring
systems; and the nitrogen, carbon or sulfur atoms in the
heterocyclic ring system radical may be optionally oxidized; the
nitrogen atom may be optionally quaternized; and the heterocyclic
ring system may be partially or fully saturated or aromatic. The
heterocyclic ring system may be attached to the main structure at
any heteroatom or carbon atom which results in the creation of a
stable compound. Examples of such heterocyclic radicals include,
but are not limited to, azepinyl, acridinyl, benzimidazolyl,
benzothiazolyl, benzoxazolyl, benzopyranyl, benzopyranonyl,
benzofuranyl, benzofuranonyl, benzothienyl, carbazolyl, cinnolinyl,
decahydroisoquinolyl, dioxolanyl, furanyl, isothiazolyl,
quinuclidinyl, imidazolyl, imidazolinyl, imidazolidinyl,
isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,
indanyl, indolizinyl, isoxazolyl, isoxazolidinyl, morpholinyl,
naphthyridinyl, oxadiazolyl, octahydroindolyl, octahydroisoindolyl,
2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,
2-oxoazepinyl, oxazolyl, oxazolidinyl, piperidinyl, piperazinyl,
4-piperidonyl, phenazinyl, phenothiazinyl, phenoxazinyl,
phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrrolidinyl,
pyrazolyl, pyrazolidinyl, pyridinyl, pyrazinyl, pyrimidinyl,
pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl,
isoquinolinyl, thiazolyl, thiazolidinyl, thiadiazolyl, triazolyl,
tetrazolyl, tetrahydrofuryl, triazinyl, tetrahydropyranyl, thienyl,
thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl
sulfone.
[0155] "Heterocyclyl" refers to a heterocyclic ring system as
defined above. Unless stated otherwise specifically in the
specification, the term "heterocyclyl" is meant to include a
heterocyclic ring system as defined above which is optionally
substituted by one or more substituents selected from the group
consisting of hydroxy, mercapto, halo, alkyl, alkenyl, alkynyl,
phenyl, phenylalkyl, phenylalkenyl, alkoxy, phenoxy, phenylalkoxy,
haloalkyl, haloalkoxy, formyl, nitro, cyano, amidino, cycloalkyl,
hydroxyalkyl, alkoxyalkyl, phenoxyalkyl, phenylalkoxyalkyl, amino,
monoalkylamino, dialkylamino, monophenylamino,
monophenylalkylamino, aminoalkyl, monoalkylaminoalkyl,
dialkylaminoalkyl, monophenylaminoalkyl, monophenylalkylaminoalkyl,
carboxy, alkoxycarbonyl, phenylcarbonyl, benzylcarbonyl,
alkylcarbonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl,
monoalkylaminocarbonyl, dialkylaminocarbonyl, phenylaminocarbonyl,
aminocarbonylalkyl, monoalkylaminocarbonylalkyl,
dialkylaminocarbonylalkyl, ureido, monoalkylureido,
monophenylureido, monobenzylureido, as defined herein.
[0156] "Heterocyclylalkyl" refers to a radical of the formula
--R.sub.aR.sub.g where R.sub.a is an alkyl radical as defined above
and R.sub.g is a heterocyclyl radical as defined above, e.g.,
indolinylmethyl or imidazolylmethyl, and the like.
[0157] "Heterocyclylamino" refers to a radical of the formula
--N(H)--R.sub.g where R.sub.g is a heterocyclyl radical as defined
above, e.g., oxazol-2-ylamino; piperidin-4-ylamino, and the
like.
[0158] "Heterocyclylaminoalkyl" refers to a radical of the formula
--R.sub.a--N(H)--R.sub.g where R.sub.a is an alkyl radical as
defined above and R.sub.g is a heterocyclyl radical as defined
above, e.g., oxazol-2-ylaminomethyl, 2-(oxazol-2-ylamino)ethyl,
piperidin4-ylaminomethyl, 2-(piperidin-4-ylamino)ethyl, and the
like.
[0159] "Heterocyclylcarbonylamino" refers to a radical of the
formula --N(H)--C(O)--R.sub.g where R.sub.g is a heterocyclyl
radical as defined above, e.g., piperidin-4-ylcarbonylamino,
furan-2-ylcarbonylamino, morpholin-4-ylcarbonylamino, and the
like.
[0160] "Heterocyclylcarbonylaminoalkyl" refers to a radical of the
formula --R.sub.a--N(H)--C(O)--R.sub.g where R.sub.a is an alkyl
radical as defined above and R.sub.g is a heterocyclyl radical as
defined above, e.g., piperidin-4-ylcarbonylaminomethyl,
2-(furan-2-ylcarbonylamino)ethyl- ,
1-(morpholin-4-ylcarbonylamino)ethyl, and the like.
[0161] "Mercapto" refers to the radical --SH.
[0162] "Mercaptoalkyl" refers to a radical of the formula
--R.sub.a--SH where R.sub.a is an alkyl radical as defined above,
e.g., mercaptomethyl, 2-mercaptoethyl, 3-mercaptopropyl,
2-mercaptobutyl and the like.
[0163] "Monoalkylamino" refers to a radical of the formula
--N(H)R.sub.a where R.sub.a is an alkyl radical as defined above,
e.g., methylamino, ethylamino, propylamino, and the like.
[0164] "Monoalkylaminoalkyl" refers to a radical of the formula
--R.sub.a--N(H)R.sub.a where each R.sub.a is independently an alkyl
radical as defined above, e.g., methylaminomethyl,
ethylaminomethyl, 2-(propylamino)ethyl, and the like.
[0165] "(Monoalkylamino)aralkyl" refers to a radical of the formula
--R.sub.d--N(H)R.sub.a where R.sub.a is an alkyl radical a defined
above and R.sub.d is an aralkyl radical as defined above, e.g.,
(methylamino)(phenyl)methyl,
1-(ethylamino)-1-(4-methoxyphenyl)ethyl,
2-(isopropylamino)-3-(3-chlorophenyl)propyl, and the like.
[0166] "Monoarylamino" refers to a radical of the formula
--N(H)R.sub.b where R.sub.b is an aryl radical as defined above,
e.g., phenylamino, (4-methoxyphenyl)amino,
(3,4,5-trimethoxyphenyl)amino and the like.
[0167] "Monoarylaminoalkyl" refers to a radical of the formula
--R.sub.a--N(H)R.sub.b where R.sub.a is an alkyl radical as defined
above and R.sub.b is an aryl radical as defined above, e.g.,
phenylaminomethyl, 2-((4-methoxyphenyl)amino)ethyl,
3-((3,4,5-trimethoxyphenyl)amino)propyl, and the like.
[0168] "Monoaralkylamino" refers to a radical of the formula
--N(H)R.sub.d where R.sub.d is an aralkyl radical as defined above,
e.g., benzylamino, (3,4,5-trimethoxybenzyl)amino,
(4-chlorobenzyl)amino,and the like.
[0169] "Monoaralkylaminoalkyl" refers to a radical of the formula
--R.sub.a--N(H)R.sub.d where R.sub.a is an alkyl radical as defined
above and R.sub.d is an aralkyl radical as defined above, e.g.,
benzylaminomethyl, (3-phenylpropyl)aminomethyl,
2-(benzylamino)ethyl, and the like.
[0170] "Monoalkylaminocarbonyl" refers to a radical of the formula
--C(O)N(H)R.sub.a where R.sub.a is an alkyl radical as defined
above, e.g., methylaminocarbonyl, ethylaminocarbonyl,
propylaminocarbonyl, and the like.
[0171] "Monoalkylaminocarbonylalkyl" refers to a radical of the
formula --R.sub.a--C(O)N(H)R.sub.a where each R.sub.a is
independently an alkyl radical as defined above, e.g.,
methylaminocarbonylmethyl, 2-(ethylaminocarbonyl)ethyl,
3-(propylaminocarbonyl)propyl, and the like.
[0172] "Monoarylaminocarbonyl" refers to a radical of the formula
--C(O)N(H)R.sub.b where R.sub.b is an aryl radical as defined
above, e.g., phenylaminocarbonyl,
(3,4,5-tris(trifluoromethoxy)phenyl)-aminocarb- onyl,
(4-chlorophenyl)aminocarbonyl, and the like.
[0173] "Monoarylaminocarbonylalkyl" refers to a radical of the
formula --R.sub.a--C(O)N(H)R.sub.b where R.sub.a is an alkyl
radical as defined above and R.sub.b is an aryl radical as defined
above, e.g., phenylaminocarbonylmethyl,
2-((4-chlorophenyl)aminocarbonyl)ethyl,
3-((3,4,5-trimethoxyphenyl)aminocarbonyl)propyl, and the like.
[0174] "Monoaralkylaminocarbonyl" refers to a radical of the
formula --C(O)N(H)R.sub.d where R.sub.d is an aralkyl radical as
defined above, e.g., benzylaminocarbonyl,
(3,4,5-tns(trifluoromethoxy)benzyl)-aminocarbo- nyl,
(4-chlorobenzyl)aminocarbonyl, and the like.
[0175] "Monoaralkylaminocarbonylalkyl" refers to a radical of the
formula --R.sub.a--C(O)N(H)R.sub.d where R.sub.a is an alkyl
radical as defined above and R.sub.d is an aralkyl radical as
defined above, e.g., benzylaminocarbonylmethyl,
2-((4-chlorobenzyl)aminocarbonyl)ethyl,
3-((3,4,5-trimethoxybenzyl)aminocarbonyl)propyl, and the like.
[0176] "(Monoalkylaminocarbonylalkyl)aminocarbonyl" refers to a
radical of the formula --C(O)--N(H)--R.sub.a--C(O)--N(H)R.sub.a
where each R.sub.a is independently an alkyl radical as defined
above, e.g., (methylaminocarbonylmethyl)aminocarbonyl,
(2-(methylaminocarbonyl)ethyl)a- minocarbonyl,
(1-(ethylaminocarbonyl)ethyl)aminocarbonyl, and the like.
[0177] "Monoalkylalaninamido" refers to radical of the formula
--N(H)--C(O)--C(CH.sub.3)H--N(H)R.sub.a where R.sub.a is an alkyl
radical as defined above and the attached nitrogen is designated as
"N" and the other nitrogen (having the R.sub.a substituent) is
designated as "N", e.g., N'-methylalanimido, N'-ethylalanimido, and
the like.
[0178] "Monoalkylglycinamido" refers to a radical of the formula
--N(H)--C(O)--CH.sub.2--N(H)R.sub.a where R.sub.a is an alkyl
radical as defined above and the attaching nitrogen is designated
as "N" and the other nitrogen (having the R.sub.a substituent) is
designated as "N", e.g., N'-methylglycinamido, N'-ethylglycinamido,
and the like.
[0179] "(Monoarylaminocarbonyl)glycinamido" refers to a radical of
the formula --N(H)--C(O)--CH.sub.2--N(H)--C(O)--N(H)R.sub.b where
R.sub.b is an aryl radical as defined above, e.g.,
((4-phenoxyphenyl)aminocarbonyl)g- lycinamido,
((4-chlorophenyl)aminocarbonyl)glycinamido,
(phenylaminocarbonyl)glycinamido, and the like.
[0180] "(Monoarylaminocarbonyl)(alkyl)glycinamido" refers to a
radical of the formula
--N(H)--C(O)--CH.sub.2--N(R.sub.a)--C(O)--N(H)R.sub.b where R.sub.a
is an alkyl radical as defined above and R.sub.b is an aryl radical
as defined above and the nitrogen to which R.sub.a is attached is
designated as "N", e.g.,
((4-phenoxyphenyl)aminocarbonyl)(N'-methyl)glyci- namido,
((4-chlorophenyl)aminocarbonyl)(N'-ethyl)g lycinamido,
(phenylaminocarbonyl)(N'-methyl)glycinamido, and the like.
[0181] "(Monoaralkylaminocarbonyl)glycinamido" refers to a radical
of the formula --N(H)--C(O)--CH.sub.2--N(H)--C(O)--N(H)R.sub.d
where R.sub.d is an aralkyl radical as defined above, e.g.,
((4-phenoxybenzyl)aminocarbony- l)glycinamido,
((4-chlorobenzyl)aminocarbonyl)glycinamido,
(benzylaminocarbonyl)glycinamido, and the like.
[0182] "(Monoaralkylaminocarbonyl)(alkyl)glycinamido" refers to a
radical of the formula
--N(H)--C(O)--CH.sub.2--N(R.sub.a)--C(O)--N(H)R.sub.d where R.sub.a
is an alkyl radical as defined above and R.sub.d is an aralkyl
radical as defined above and the nitrogen to which the R.sub.a is
attached is designated as "N", e.g.,
((4-phenoxybenzyl)aminocarbonyl)(N'-- methyl)glycinamido,
((4-chlorobenzyl)aminocarbonyl)(N'-ethyl)glycinamido,
(benzylaminocarbonyl)(N'-methyl)glycinamido, and the like.
[0183] "Monoalkylureido" refers to a radical of the formula
--N(H)--C(O)--N(H)R.sub.a or a radical of the formula
--N(R.sub.a)--C(O)--NH.sub.2 where R.sub.a is an alkyl radical as
defined above and the attaching nitrogen is designated as "N" and
the other nitrogen is designated as "N", e.g., N'-methylureido,
N'-ethylureido, N'-propylureido, N-methylureido, N-ethylureido,
N-propylureido, and the like.
[0184] "Monophenylureido" refers to a radical of the formula
--N(H)--C(O)--N(H)R.sub.h where R.sub.h is a phenyl radical as
defined above, and the attaching nitrogen is designated as "N" and
the other nitrogen is designated as "N", e.g., N'-phenylureido,
N'-(4-nitrophenyl)ureido, N'-(3-chlorophenyl)ureido, and the
like.
[0185] "Monobenzylureido" refers to a radical of the formula
--N(H)--C(O)--N(H)--CH.sub.2--R.sub.h where R.sub.h is a phenyl
radical as defined above, and the attaching nitrogen is designated
as "N" and the other nitrogen is designated as "N", e.g.,
N'-benzylureido, N'-(4-nitrobenzyl)ureido,
N'-(3-chlorobenzyl)ureido, and the like.
[0186] "Monohaloalkylureido" refers to a radical of the formula
--N(H)--C(O)--N(H)R.sub.f or a radical of the formula
--N(R.sub.f)--C(O)--NH.sub.2 where R.sub.f is a haloalkyl radical
as defined above and the attaching nitrogen is designated as "N"
and the other nitrogen is designated as "N", e.g.,
N'-chloromethylureido, N'-(2,2-difluoroethyl)ureido,
N'-(3-chloropropyl)ureido, N-(trifluoromethyl)ureido,
N-(pentafluoroethyl)ureido, N-(3-iodopropyl)ureido, and the
like.
[0187] "Monoarylureido" refers to a radical of the formula
--N(H)--C(O)--N(H)R.sub.b or a radical of the formula
--N(R.sub.b)--C(O)--NH.sub.2 where R.sub.b is an aryl radical as
defined above and the attaching nitrogen is designated as "N" and
the other nitrogen is designated as "N", e.g., N'-phenylureido,
N'-(4-methoxyphenyl)ureido, N'-(3-chlorophenyl)ureido,
N-phenylureido, N-(2-trifluoromethylphenyl)ureido,
N-(4-chlorophenyl)ureido, and the like.
[0188] "Monoaralkylureido" refers to a radical of the formula
--N(H)--C(O)--N(H)R.sub.d or a radical of the formula
--N(R.sub.d)--C(O)--NH.sub.2 where R.sub.d is an aralkyl radical as
defined above and the attaching nitrogen is designated as "N" and
the other nitrogen is designated as "N", e.g., N'-benzylureido,
N'-(4-methoxybenzyl)ureido, N'-(3-chlorobenzyl)ureido,
N-benzylureido, N-(2-trifluoromethylbenzyl)ureido,
N-(4-chlorobenzyl)ureido, and the like.
[0189] "(Monoalkyl)(monoaryl)ureido" refers to a radical of the
formula --N(R.sub.a)--C(O)--N(R.sub.b)H, or a radical of the
formula --N(R.sub.b)--C(O)--N(R.sub.a)H, or a radical of the
formula --N(H)--C(O)--N(R.sub.a)(R.sub.b) where R.sub.a is an alkyl
radical as defined above and R.sub.b is an aryl radical as defined
above, and where the attaching nitrogen is designated as "N" and
the other nitrogen is designated as "N", e.g.,
N-methyl-N'-phenylureido, N-phenyl-N'-ethylureido,
N-methyl-N'-(4-fluorophenyl)ureido,
N'-ethyl-N'-(3-cyanophenyl)ureido, and the like.
[0190] "Monoalkylureidoalkyl" refers to a radical of the formula
--R.sub.a--N(H)--C(O)--N(H)R.sub.a or a radical of the formula
--R.sub.a--N(R.sub.a)--C(O)--NH.sub.2 where R.sub.a is an alkyl
radical as defined above and the attaching nitrogen is designated
as "N" and the other nitrogen is designated as "N", e.g.,
N'-methylureidomethyl, 2-(N'-ethylureido)ethyl,
1-(N'-propylureido)ethyl, N-methylureidomethyl,
2-(N-ethylureido)ethyl, 1-(N-propylureido)ethyl, and the like.
[0191] "Monohaloalkylureidoalkyl" refers to a radical of the
formula --R.sub.a--N(H)--C(O)--N(H)R.sub.f or a radical of the
formula --R.sub.a--N(R.sub.f)--C(O)--NH.sub.2 where R.sub.a is an
alkyl radical as defined above and R.sub.f is a haloalkyl radical
as defined above and the attaching nitrogen is designated as "N"
and the other nitrogen is designated as "N", e.g.,
N'-chloromethylureidomethyl, 2-(N'-(2,2-difluoroethyl)ureido)ethyl,
1-(N'-(3-chloropropyl)ureido)ethyl- ,
N-(trifluoromethyl)ureidomethyl,
2-(N-(pentafluoroethyl)ureido)ethyl,
1-(N-(3-iodopropyl)ureido)ethyl, and the like.
[0192] "Monoarylureidoalkyl" refers to a radical of the formula
--R.sub.a--N(H)--C(O)--N(H)R.sub.b or a radical of the formula
--R.sub.a--N(R.sub.b)--C(O)--NH.sub.2 where R.sub.a is an alkyl
radical as defined above and R.sub.b is an aryl radical as defined
above and the attaching nitrogen is designated as "N" and the other
nitrogen is designated as "N", e.g., N'-phenylureidomethyl,
2-(N'-(4-methoxyphenyl)ur- eido)ethyl,
1-(N'-(3-chlorophenyl)ureido)ethyl, N-phenylureidomethyl,
2-(N-(2-trifluoromethylphenyl)ureido)ethyl,
1-(N-(4-chlorophenyl)ureido)e- thyl, and the like.
[0193] "Monoaralkylureidoalkyl" refers to a radical of the formula
--R.sub.a--N(H)--C(O)--N(H)R.sub.d or a radical of the formula
--R.sub.a--N(R.sub.d)--C(O)--NH.sub.2 where R.sub.a is an alkyl
radical as defined above and R.sub.b is an aralkyl radical as
defined above and the attaching nitrogen is designated as "N" and
the other nitrogen is designated as "N", e.g.,
N'-benzylureidomethyl, 2-(N'-(4-methoxybenzyl)ur- eido)ethyl,
1-(N'-(3-chlorobenzyl)ureido)ethyl, N-benzylureidomethyl,
2-(N-(2-trifluoromethylbenzyl)ureido)ethyl, 1-(N-(4-chlorobenzyl)u
reido)ethyl, and the like.
[0194] "Monophenyiamino" refers to an amino radical substituted by
a phenyl radical as defined herein.
[0195] "Monophenylalkylamino" refers to an amino radical
substituted by a phenylalkyl group as defined below, e.g.,
benzylamino, 2-(benzyl)butylamino, and the like.
[0196] "Monophenylaminoalkyl" refers to an alkyl radical as defined
above substituted by a monophenylamino group as defined above,
e.g., (phenylamino)methyl, 2-(1-(phenyl)ethylamino)ethyl, and the
like.
[0197] "Monophenylalkylaminoalkyl" refers to an alkyl radical as
defined above substituted by a monophenylalkylamino group as
defined above, e.g., (benzylamino)methyl,
2-(2-benzyl)butylamino)ethyl, and the like.
[0198] "Nitro" refers to the radical --NO.sub.2.
[0199] "Oxo" refers to the subsituent .dbd.O.
[0200] "Optional" or "optionally" means that the subsequently
described event of circumstances may or may not occur, and that the
description includes instances where said event or circumstance
occurs and instances in which it does not. For example, "optionally
substituted aryl" means that the aryl radical may or may not be
substituted and that the description includes both substituted aryl
radicals and aryl radicals having no substitution.
[0201] "Phenyl" refers to the benzene radical optionally
substituted by one or more substituents selected from the group
consisting of hydroxy, halo, alkyl, haloalkyl, alkoxy, alkenyl,
nitro, cyano, amino, monoalkylamino, dialkylamino, alkylcarbonyl,
carboxy, alkoxycarbonyl, and aminocarbonyl.
[0202] "Phenoxy" refers to the radical of the formula --OR.sub.h
where R.sub.h is phenyl as defined above.
[0203] "Phenylalkyl" refers to an alkyl radical as defined above
substituted by a phenyl radical, e.g., benzyl, and the like.
[0204] "Phenylalkenyl" refers to an alkenyl radical as defined
above substituted by a phenyl radical, e.g., 3-phenylprop-2-enyl,
and the like.
[0205] "Phenylalkoxy" refers to a radical of the formula --OR.sub.i
where R.sub.i is a phenylalkyl radical as defined above, e.g.,
benzyloxy, and the like.
[0206] "Phenylalkoxyalkyl" refers to an alkyl radical as defined
above substituted by a phenylalkoxy radical as defined above, e.g.,
benzyloxymethyl, and the like.
[0207] "Phenylcarbonyl" refers to a radical of the formula
--C(O)--R.sub.h where R.sub.h is a phenyl radical as defined above,
e.g., (4-chlorophenyl)carbonyl, (4-fluorophenyl)carbonyl, and the
like.
[0208] "Phenylaminocarbonyl" refers to a radical of the formula
--C(O)--N(H)--R.sub.h where R.sub.h is a phenyl radical as defined
above, e.g., (4-chlorophenyl)aminocarbonyl,
(4-methoxyphenyl)aminocarbonyl, and the like.
[0209] "Pharmaceutically acceptable counterion"" refers to those
anions which retain the biological effectiveness and properties of
the parent compound, which are not biologically or otherwise
undesirable. Examples of such anions may be found in Berge, S. M.
et al., Journal of Pharmaceutical Sciences (1977), Vol. 66, No. 1,
pp. 1-19.
[0210] "Pharmaceutically acceptable salt" includes both acid and
base addition salts.
[0211] "Pharmaceutically acceptable acid addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free bases, which are not biologically or
otherwise undesirable, and which are formed with inorganic acids
such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid and the like, and organic acids such as
acetic acid, propionic acid, pyruvic acid, maleic acid, malonic
acid, succinic acid, fumaric acid, tartaric acid, citric acid,
benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic
acid, p-toluenesulfonic acid, salicylic acid, and the like.
[0212] "Pharmaceutically acceptable base addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free acids, which are not biologically or
otherwise undesirable. These salts are prepared from addition of an
inorganic base or an organic base to the free acid. Salts derived
from inorganic bases include, but are not limited to, the sodium,
potassium, lithium, ammonium, calcium, magnesium, zinc, aluminum
salts and the like. Preferred inorganic salts are the ammonium,
sodium, potassium, calcium, and magnesium salts. Salts derived from
organic bases include, but are not limited to, salts of primary,
secondary, and tertiary amines, substituted amines including
naturally occurring substituted amines, cyclic amines and basic ion
exchange resins, such as isopropylamine, trimethylamine,
diethylamine, triethylamine, tripropylamine, ethanolamine,
2-dimethylaminoethanol, 2-diethylaminoethanol, trimethamine,
dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,
hydrabamine, choline, betaine, ethylenediamine, glucosamine,
methylglucamine, theobromine, purines, piperazine, piperidine,
N-ethylpiperidine, polyamine resins and the like. Particularly
preferred organic bases are isopropylamine, diethylamine,
ethanolamine, trimethylamine, dicyclohexylamine, choline and
caffeine.
[0213] "THF" refers to tetrahydrofuran.
[0214] "Therapeutically effective amount" refers to that amount of
a compound of formula (I) which, when administered to a human in
need of such administration, is sufficient to effect treatment, as
defined below, for myocarditis. The amount of a compound of formula
(I) which constitutes a "therapeutically effective amount" will
vary depending on the compound, the severity of the disorder, and
the age of the human to be treated, but can be determined routinely
by one of ordinary skill in the art having regard to his own
knowledge and to this disclosure.
[0215] "Treating" or "treatment" as used herein cover the treatment
of myocarditis in a human; and include:
[0216] (i) preventing the disorder from occurring in a human, in
particular, when such human is predisposed to the disorder but has
not yet been diagnosed as having it;
[0217] (ii) inhibiting the disorder, i.e., arresting its
development; or
[0218] (iii) relieving the disorder, i.e., causing regression of
the disorder.
[0219] "Ureido" refers to a radical of the formula
--N(H)--C(O)--NH.sub.2.
[0220] "Ureidoalkyl" refers to a radical of the formula
--R.sub.a--N(H)C(O)NH.sub.2 where R.sub.a is an alkyl radical as
defined above, e.g., ureidomethyl, 2-(ureido)ethyl,
3-(ureido)propyl, and the like.
[0221] It is understood from the above definitions and examples
that for radicals containing a substituted alkyl group any
substitution thereon can occur on any carbon of the alkyl
group.
[0222] The compounds of the invention, or their pharmaceutically
acceptable salts, may have asymmetric carbon atoms in their
structure. The compounds of the invention and their
pharmaceutically acceptable salts may therefore exist as single
stereoisomers, racemates, and as mixtures of enantiomers and
diastereomers. All such single stereoisomers, racemates and
mixtures thereof are intended to be within the scope of this
invention. Absolute configuration of certain carbon atoms within
the compounds, if known, are indicated by the appropriate absolute
descriptor R or S. The descriptor "trans" is used to indicate that
the R.sup.1a or the R.sup.1b substituents are on opposite sides of
the piperazine plane. The descriptor "cis" is used to indicate that
the R.sup.1a or the R.sup.1b substituents are on the same side of
the piperazine plane.
[0223] The nomenclature used herein is a modified form of the
I.U.P.A.C. system wherein the compounds of the invention are named
as piperazine derivatives. For example, a compound of formula (Ia)
wherein R.sup.6 is --C(O)--, R.sup.5 is ethylene, R.sup.4 is --O--,
R.sup.1a is in the 2-position of the piperazine ring and is
ethoxycarbonyl, R.sup.2 is 2-(ethylamino)ethyl in the 4-position of
the phenyl ring and R.sup.3 is naphthalen-1-yl substituted at the
4-position by methoxy, i.e., the compound of the following formula:
3
[0224] is named herein as
1-(2-((4-methoxynaphthalen-1-yl)oxy)ethyl)carbon-
yl-2-ethoxycarbonyl-4-(4-(2-(ethylamino)ethyl)benzyl)piperazine.
[0225] Utility and Administration
[0226] A. Utility
[0227] As supported by the Examples by the examples herein,
compounds of the type disclosed herein are useful in treating
myocarditis.
[0228] B. Testing Procedures
[0229] Animals
[0230] Male Lewis rats (7-weeks-old; body weights 200 to 250 g)
were purchased from Sankyo Laboratories. They were fed a standard
diet and water and were maintained in compliance with animal
welfare guide lines of the Institute of Experimental Animals, Tokyo
Medical and Dental University.
[0231] Antigen and Immunization
[0232] Purified porcine cardiac myosin (Sigma Chemical Co.) was
dissolved in 0.01 M phosphate-buffered saline (PBS) and emulsified
with an equal volume of complete Freund's adjuvant (Difco)
supplemented with Mycobactedium tuberculosis H37RA (Difco) at a
concentration of 10 mg/mL. On day 0, rats were injected in the
footpads subcutaneous with 0.2 mL of emulsion, yielding an
immunizing dose of 1.0 mg/body of cardiac myosin per rat.
[0233] Preparation of Stock Solution of Piperazine Derivative
[0234] A 25 mg/ml sterile saline solution of
(2R)-1-((4-chloro-2-(ureido)p-
henoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine in 40%
cyclodextrin(Sigma) was prepared by dissolving the compound into
40% cyclodextrin in saline. The mixture was shaken followed by the
addition of HCl. The mixture was stirred to dissolve the solute.
After dissolution was complete, 1.sub.MKOH was added to raise the
pH to 4.5.
[0235] Treatment
[0236] Rats were administered subcutaneously with stock solution of
(2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorob-
enzyl)piperazine, from day 0 (group B.times.0) or from day 14
(group B.times.14) every day (50 mg/kg, twice per day) and were
sacrificed on day 21. As controls, groups C1 and C2 were treated
with 40% cyclodextrin/saline.
[0237] C. General Administration
[0238] Administration of the compounds of the invention, or their
pharmaceutically acceptable salts, in pure form or in an
appropriate pharmaceutical composition, can be carried out via any
of the accepted modes of administration or agents for serving
similar utilities. Thus, administration can be, for example,
orally, nasally, parenterally, topically, transdermally, or
rectally, sublingually, intramuscular, subcutaneously, or
intravenously in the form of solid, semi-solid, lyophilized powder,
or liquid dosage forms, such as for example, tablets,
suppositories, pills, soft elastic and hard gelatin capsules,
powders, solutions, suspensions, or aerosols, or the like,
preferably in unit dosage forms suitable for simple administration
of precise dosages. The compositions will include a conventional
pharmaceutical carrier or excipient and a compound of the invention
as the/an active agent, and, in addition, may include other
medicinal agents, pharmaceutical agents, carriers, adjuvants,
etc.
[0239] Generally, depending on the intended mode of administration,
the pharmaceutically acceptable compositions will contain about 1%
to about 99% by weight of a compound(s) of the invention, or a
pharmaceutically acceptable salt thereof, and 99% to 1% by weight
of one or more suitable pharmaceutical excipient(s). Preferably,
the composition will be about 5% to 75% by weight of a compound(s)
of the invention, or a pharmaceutically acceptable salt thereof,
with the rest being suitable pharmaceutical excipients.
[0240] The preferred route of administration is oral, using a
convenient daily dosage regimen which can be adjusted according to
the degree of severity of the disease-state to be treated. For such
oral administration, a pharmaceutically acceptable composition
containing a compound(s) of the invention, or a pharmaceutically
acceptable salt thereof, is formed by the incorporation of any of
the normally employed excipients. Such excipients include non-toxic
and chemically compatible fillers, binders, disintegrants, buffers,
preservatives, anti-oxidants, lubricants, flavorings, thickeners,
coloring agents, emulsifiers, and the like, for example,
pharmaceutical grades of mannitol, lactose, starch, pregelatinized
starch, magnesium stearate, sodium saccharine, talcum, cellulose
ether derivatives, glucose, gelatin, sucrose, citrate,
cyclodextrin, propyl gallate, and the like. Such compositions take
the form of solutions, suspensions, tablets, pills, capsules,
powders, sustained release formulations and the like.
[0241] Preferably such compositions will take the form of capsule,
caplet or tablet and therefore will also contain a diluent such as
lactose, sucrose, dicalcium phosphate, and the like; a disintegrant
such as croscarmellose sodium or derivatives thereof; a lubricant
such as magnesium stearate and the like; and a binder such as a
starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose ether
derivatives, and the like.
[0242] The compounds of the invention, or their pharmaceutically
acceptable salts, may also be formulated into a suppository using,
for example, about 0.5% to about 50% active ingredient disposed in
a carrier that slowly dissolves within the body, e.g.,
polyoxyethylene glycols and polyethylene glycols (PEG), e.g., PEG
1000 (96%) and PEG 4000 (4%), and propylene glycol.
[0243] Liquid pharmaceutically administrable compositions can, for
example, be prepared by dissolving, dispersing, etc., a compound(s)
of the invention (about 0.5% to about 20%), or a pharmaceutically
acceptable salt thereof, and optional pharmaceutical adjuvants in a
carrier, such as, for example, water, saline, aqueous dextrose,
aqueous cyclodextrin, glycerol, ethanol and the like, to thereby
form a solution or suspension.
[0244] If desired, a pharmaceutical composition of the invention
may also contain minor amounts of auxiliary substances such as
wetting or emulsifying agents, pH buffering agents, antioxidants,
and the like, such as, for example, citric acid, sorbitan
monolaurate, triethanolamine oleate, butylated hydroxytoluene,
etc.
[0245] Actual methods of preparing such dosage forms are known, or
will be apparent, to those skilled in this art; for example, see
Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing
Company, Easton, Pa., 1990). The composition to be administered
will, in any event, contain a therapeutically effective amount of a
compound of the invention, or a pharmaceutically acceptable salt
thereof, for treatment of myocarditis.
[0246] The compounds of the invention, or their pharmaceutically
acceptable salts, are administered in a therapeutically effective
amount which will vary depending upon a variety of factors
including the activity of the specific compound employed, the
metabolic stability and length of action of the compound, the age,
body weight, general health, sex, diet, mode and time of
administration, rate of excretion, drug combination, the severity
of the disease-state, and the host undergoing therapy. Generally, a
therapeutically effective daily dose is from about 0.014 mg to
about 14.0 mg/kg of body weight per day of a compound of the
invention, or a pharmaceutically acceptable salt thereof;
preferably, from about 0.14 mg to about 10.0 mg/kg of body weight
per day; and most preferably, from about 1.4 mg to about 7.0 mg/kg
of body weight per day. For example, for administration to a 70 kg
person, the dosage range would be from about 1.0 mg to about 1.0
gram per day of a compound of the invention, or a pharmaceutically
acceptable salt thereof, preferably from about 10 mg to about 700
mg per day, and most preferably from about 100 mg to about 500 mg
per day.
[0247] D. Combinations
[0248] The compounds of the present invention can be administered
alone or in combination with one or more additional other
therapeutic agents including:
[0249] Diuretics;
[0250] ACE Inhibitors;
[0251] Angiotensin Receptor Antagonists;
[0252] Beta Adrenoreceptor Blockers;
[0253] Carvedilol and Labetolol (mixed beta-blocker with alpha-1
blocking properties);
[0254] Vasodilators (e.g., Sodium Nitroprusside);
[0255] Positive Inotropic Agents (e.g., Dobutamine)
[0256] E. Preferred Compounds
[0257] Preferred compounds of the present invention include all the
preferred compounds identified in U.S. Pat. No. 6,207,665 and WO
98/56771.
[0258] More preferred compounds include compounds of formula la
wherein:
[0259] R.sup.3 is a carbocylic ring system substituted by one or
more substituents independently selected from the group consisting
of hydrogen, hydroxy, hydroxysulfonyl, halo, alkyl, mercapto,
mercaptoalkyl, alkylthio, alkylsulfinyl, alkylsufonyl,
arylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl,
alkylsulfonylalkyl, alkoxy, hydroxyalkoxy, aryloxy, haloalkyl,
formyl, formylalkyi, nitro, nitroso, cyano, aralkoxy, haloalkoxy,
aminoalkoxy, cycloalkyl, cycloalkylalkyl, (hydroxy)cycloalkylalkyl,
cycloalkylamino, cycloalkylaminoalkyl, cyanoalkyl, alkenyl,
alkynyl, aryl, aralkyl, aralkenyl, hydroxyalkyl, (hydroxy)aralkyl,
(monoalkylamino)aralkyl, (hydroxyalkyl)hioalkyl, hydroxyalkenyl,
hydroxyalkynyl, alkoxyalkyl, (alkoxy)aralkyl, aryloxyalkyl,
aralkoxyalkyl, amino, monoalkylamino, dialkylamino, monoarylamino,
monoaralkylamino, aminoalkylamino, heterocyclylamino,
(cycloalkylalkyl)amino, alkylcarbonylamino, alkoxycarbonylamino,
alkenylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino,
heterocyclylcarbonylamino, haloalkylcarbonylamino,
alkoxyalkylcarbonylamino, alkoxycarbonylalkylcarbonylamino,
(alkylcarbonyl)(alkyl)amino, (alkoxycarbonyl)(alkyl)amino,
alkylsulfonylamino, aminoalkyl, monoalkylaminoalkyl,
dialkylaminoalkyl, hydroxyalkylaminoalkyl, monoarylaminoalkyl,
monoaralkylaminoalkyl, alkylcarbonylaminoalkyl,
arylcarbonylaminoalkyl, (alkylcarbonyl)(alkyl)am- inoalkyl,
(cycloalkyalkyl)aminoalkyl, alkoxycarbonylaminoalkyl,
alkoxycarbonylalkylcarbonylaminoalkyl,
(alkoxycarbonyl)(alkyl)aminoalkyl, alkylsulfonylaminoalkyl,
(alkylsulfonyl)(alkyl)aminoalkyl, arylsulfonylaminoalkyl,
(arylsulfonyl)(alkyl)aminoalkyl, heterocyclylaminoalkyl, carboxy,
alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, arylcarbonyl,
aralkylcarbonyl, (hydroxyalkoxy)carbonyl, carboxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
alkoxyalkylcarbonyloxyalkyl, dialkylaminocarbonyloxyalkyl,
alkylcarbonylalkyl, arylcarbonylalkyl, aralkylcarbonylalkyl,
aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl,
monoarylaminocarbonyl, monoaralkylaminocarbonyl,
(aminocarbonylalkyl)amin- ocarbonyl,
(monoalkylaminocarbonylalkyl)aminocarbonyl,
(carboxyalkyl)aminocarbonyl, (alkoxycarbonylalkyl)aminocarbonyl,
(aminoalkyl)aminocarbonyl, (hydroxyalkyl)aminocarbonyl,
aminocarbonylalkyl, monoalkylaminocarbonylalkyl,
dialkylaminocarbonylalky- l, monoarylaminocarbonylalkyl,
monoaralkylaminocarbonylalkyl, amidino, hydroxyamidino, guanidino,
ureido, monoalkylureido, monoarylureido, monoaralkylureido,
monohaloalkylureido, (monoalkyl)(monoaryl)ureido, dialkylureido,
diarylureido, (haloalkylcarbonyl)ureido, ureidoalkyl,
monoalkylureidoalkyl, dialkylureidoalkyl, monoarylureidoalkyl,
monoaralkylureidoalkyl, monohaloalkylureidoalkyl,
(haloalkyl)(alkyl)ureid- oalkyl, (alkoxycarbonylalkyl)ureldoalkyl,
glycinamido, monoalkylglycinamido, aminocarbonylglycinamido,
(alkoxyalkylcarbonyl)glyc- inamido,
(aminocarbonyl)(alkyl)glycinamido, (alkoxycarbonylalkylcarbonyl)(-
alkyl)glycinamido, (alkoxycarbonylaminoalkylcarbonyl)glycinamido,
arylcarbonylglycinamido, (arylcarbonyl)(alkyl)glycinamido,
(monoaralkylaminocarbonyl)glycinamido,
(monoaralkylaminocarbonyl)(alkyl)g- lycinamido,
(monoarylaminocarbonyl)glycinamido, (monoarylaminocarbonyl)(al-
kyl)glycinamido, glycinamidoalkyl, alaninamido,
monoalkylalaninamido, alaninamidoalkyl, heterocyclyl and
heterocyclylalkyl.
[0260] Of this group of compounds, a preferred subgroup of
compounds is that group of compounds wherein:
[0261] R.sup.4 is --O--, --N(R.sup.7)-- or --C(R.sup.8)--;
[0262] R.sup.5 is an alkylene chain;
[0263] R.sup.7 is selected from the group consisting of hydrogen,
alkyl, aryl, aralkyl, alkylcarbonyl, alkylcarbonylalkyl,
aralkylcarbonyl, aralkylcarbonylalkyl, aminocarbonyl,
monoalkylaminocarbonyl, dialkylaminocarbonyl, and alkoxycarbonyl;
and
[0264] each R.sup.8 is independently selected from the group
consisting of hydrogen, alkyl, aryl, aralkyl, hydroxy, alkoxy,
hydroxyalkyl, alkoxyalkyl, amino, monoalkylamino, dialkylamino,
alkylcarbonylamino, cycloalkylcarbonylamino,
cycloalkylalkylcarbonylamino, alkoxycarbonylamino,
alkylsulfonylamino, arylcarbonylamino,
alkoxycarbonylalkylcarbonylamino, (alkylcarbonyl)(alkyl)amino,
aralkylcarbonylamino, (aralkylcarbonyl)(alkyl)amino,
alkylcarbonylaminoalkyl, cycloalkylcarbonylaminoalkyl,
alkoxycarbonylaminoalkyl, (alkylcarbonyl)(alkyl)aminoalkyl,
aralkylcarbonylaminoalkyl, heterocyclylcarbonylaminoalkyl,
(aralkylcarbonyl)(alkyl)aminoalkyl, arylsulfonylamino,
alkylsulfonylaminoalkyl, ureido, monoalkylureido,
monohaloalkylureido, dialkylureido, ureidoalkyl,
monoalkylureidoalkyl, dialkylureidoalkyl, monohaloalkylureidoalkyl,
aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl,
alkoxycarbonylalkyl, aminocarbonylalkyl,
monoalkylaminocarbonylalkyl, and dialkylaminocarbonylalkyl.
[0265] Of this subgroup of compounds, a preferred class of
compounds is that group of compounds wherein:
[0266] R.sup.4 is --O--;
[0267] R.sup.5 is methylene; and
[0268] R.sup.6 is --C(O)--.
[0269] Of this class of compounds, a preferred subclass of
compounds is that group of compounds wherein:
[0270] R.sup.1a is one or more substituents independently selected
from the group consisting of halo, alkyl, cycloalkyl,
cycloalkylaminoalkyl, haloalkyl, hydroxyalkyl, hydroxyalkenyl,
hydroxyalkynyl, (hydroxy)aralkyl, cyanoalkyl,
haloalkylcarbonylaminoalkyl, alkoxyalkyl, aralkoxyalkyl,
alkylthioalkyl, hydroxyalkylthioalkyl, aminoalkyl,
monoalkylaminoalkyl, dialkylaminoalkyl, monoarylaminoalkyl,
monoaralkylaminoalkyl, azidoalkyl, monoalkylureidoalkyl,
(alkoxycarbonylalkyl)ureidoalkyl, hydroxyalkylaminoalkyl,
aryloxyalkylcarbonyloxyalkyl, aralkoxyalkylcarbonyloxyalkyl,
alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, and
heterocyclylalkyl;
[0271] R.sup.2 is one or more substituents independently selected
from the group consisting of hydrogen and halo;
[0272] R.sup.3 is phenyl optionally substituted by one or more
substituents independently selected from the group consisting of
hydrogen, hydroxy, halo, alkyl, alkoxy, hydroxyalkoxy, haloalkyl,
formyl, nitro, cyano, aminoalkoxy, cycloalkyl,
cycloalkylaminoalkyl, aralkyl, hydroxyalkyl,
(monoalkylamino)aralkyl, alkoxyalkyl, amino, monoalkylamino,
dialkylamino, monoaralkylamino, alkylcarbonylamino,
alkenylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino,
heterocyclylcarbonylamino, haloalkylcarbonylamino,
alkoxyalkylcarbonylamino, alkoxycarbonylalkylcarbonylamino,
(alkylcarbonyl)(alkyl)amino, alkylsulfonylamino, aminoalkyl,
monoalkylaminoalkyl, dialkylaminoalkyl, monoarylaminoalkyl,
monoaralkylaminoalkyl, alkylcarbonylaminoalkyl,
arylcarbonylaminoalkyl, (alkylcarbonyl)(alkyl)aminoalkyl,
(cycloalkyalkyl)aminoalkyl, alkoxycarbonylaminoalkyl,
alkoxycarbonylalkylcarbonylaminoalkyl,
(alkoxycarbonyl)(alkyl)aminoalkyl, alkylsulfonylaminoalkyl,
(alkylsulfonyl)(alkyl)aminoalkyl, arylsulfonylaminoalkyl,
(arylsulfonyl)(alkyl)aminoalkyl, heterocyclylaminoalkyl, carboxy,
alkoxycarbonyl, alkylcarbonyl, (hydroxyalkoxy)carbonyl,
aminocarbonyl, monoalkylaminocarbonyl, monoarylaminocarbonyl,
(aminocarbonylalkyl)aminoc- arbonyl, (aminoalkyl)aminocarbonyl,
(hydroxyalkyl)aminocarbonyl, dialkylaminocarbonylalkyl,
hydroxyamidino, ureido, monoalkylureido, monoarylureido,
monoaralkylureido, (monoalkyl)(monoaryl)ureido,
(haloalkylcarbonyl)ureido, ureidoalkyl, monoalkylureidoalkyl,
dialkylureidoalkyl, monoarylureidoalkyl, monoaralkylureidoalkyl,
monohaloalkylureidoalkyl, (haloalkyl)(alkyl)ureidoalkyl,
(alkoxycarbonylalkyl)ureidoalkyl, glycinamido,
monoalkylglycinamido, aminocarbonylglycinamido,
(alkoxyalkylcarbonyl)glycinamido,
(aminocarbonyl)(alkyl)glycinamido,
(alkoxycarbonylalkylcarbonyl)(alkyl)gl- ycinamido,
(alkoxycarbonylaminoalkylcarbonyl)glycinamido,
arylcarbonylglycinamido, (arylcarbonyl)(alkyl)glycinamido,
(monoaralkylaminocarbonyl)glycinamido,
(monoaralkylaminocarbonyl)(alkyl)g- lycinamido,
(monoarylaminocarbonyl)glycinamido, (monoarylaminocarbonyl)(al-
kyl)glycinamido, alaninamido, heterocyclyl and
heterocyclylalkyl.
[0273] Preferred compounds within this subclass of compounds are
selected from the group consisting of the following compounds:
[0274]
(2S)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl-
)piperazine;
[0275]
1-((phenoxy)methyl)carbonyl-2-ethyl-4-(4-fluorobenzyl)piperazine;
[0276]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-ethylpiper-
azine;
[0277]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-(methoxyme-
thyl)piperazine;
[0278]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-((acetylam-
ino)methyl)piperazine;
[0279]
1-((4-chlorophenoxy)methyl)carbonyl-2-(2-((4-fluorobenzyl)amino)eth-
yl)4-(4-fluorobenzyl)piperazine;
[0280]
1-((4-chlorophenoxy)methyl)carbonyl-2-(2-((methyl)amino)ethyl)4-(4--
fluorobenzyl)piperazine;
[0281]
1-((4-chlorophenoxy)methyl)carbonyl-2-(2-((2-hydroxyethyl)amino)eth-
yl)4-(4-fluorobenzyl)piperazine;
[0282]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-((((4-chlo-
rophenoxy) -methyl)carbonyl)oxy)methyl-5-methylpiperazine;
[0283]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(ethoxycar-
bonyl)piperazine;
[0284]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(methoxyca-
rbonyl)methylpiperazine;
[0285]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-((methoxy)-
methyl)piperazine;
[0286]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-(methox-
y)ethyl)piperazine;
[0287]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-hydroxy-
-2-(4-methylphenyl)-ethyl)piperazine;
[0288]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-hydroxy-
propyl)piperazine;
[0289]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-hydroxy-
but-4-ynyl)piperazine;
[0290]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-5-(2-hydroxy-
-2-methylpropyl)piperazine;
[0291]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-hydroxy-
ethyl)piperazine;
[0292]
1-((4-chlorophenoxy)methyl)carbonyl-3-(2-((2-hydroxyethyl)amino)eth-
yl)-4-(4-fluorobenzyl)piperazine;
[0293]
(cis)4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2,3-dim-
ethylpiperazine;
[0294]
(2S,5R)-1-((4-chloro-3,5-dimethoxyphenoxy)methyl)carbonyl-2,5-dimet-
hyl-4-(4-fluorobenzyl)piperazine;
[0295]
(2S,5S)-4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2,5--
dimethylpiperazine;
[0296]
(2R,5S)-4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-me-
thyl-5-(2-methylthio)ethylpiperazine;
[0297]
(2R,5R)4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-met-
hyl-5-(benzyloxy)methyl-piperazine;
[0298]
(2R,5R)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl-4-(4-fluoroben-
zyl)-5-(((2-hydroxyethyl)thio)methyl)piperazine;
[0299]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-(N'-(ethox-
ycarbonylmethyl) ureido)methyl)piperazine;
[0300]
(2R,5S)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl-5-((amino)carb-
onyloxy)methyl-4-(4-fluorobenzyl)piperazine;
[0301]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-((acetyl)m-
ethyl)piperazine;
[0302]
(2R,5R)4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-met-
hyl-5-(1-hydroxy-1-(phenyl)methyl)piperazine;
[0303]
(2R,5R)4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-met-
hyl-5-(1-hydroxybutyl)piperazine;
[0304]
(2R,5S)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl4-(4-fluorobenz-
yl)-5-((diethylamino)methyl)piperazine;
[0305]
(2R,5S)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl-4-(4-fluoroben-
zyl)-5-((dimethylamino)methyl)piperazine;
[0306]
(2R,5S)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl-4-(4-fluoroben-
zyl)-5-(((cyclopropyl)amino)methyl)piperazine;
[0307]
(2R,5S)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl-4-(4-fluoroben-
zyl)-5-((morpholin-4-yl)methyl)piperazine;
[0308]
(2R,5R)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl-4-(4-fluoroben-
zyl)-5-((piperazin-1-yl)methyl)piperazine;
[0309]
(cis)-1-((3,4,5-trimethoxyphenoxy)methyl)carbonyl-2,6-dimethyl4-(4--
fluorobenzyl)piperazine;
[0310]
(cis)-4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2,6-di-
methylpiperazine;
[0311]
1-((phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine;
[0312]
1-((2-(acetylamino)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenz-
yl)piperazine;
[0313]
1-((4-chlorophenoxy)methyl)carbonyl-2-(2-hydroxypropyl)-4-(4-fluoro-
benzyl)piperazine;
[0314]
1-((4-chlorophenoxy)methyl)carbonyl-2-(2-hydroxybut-3-enyl)-4-(4-fl-
uorobenzyl)piperazine;
[0315]
1-((4-chlorophenoxy)methyl)carbonyl-3-trifluoromethyl4-(4-fluoroben-
zyl)piperazine; and
[0316]
(trans)-1-((4-chloro-2-((4-(2,5-di(trifluoromethyl)phenylcarbonyl)p-
iperazin-1-yl)methyl)phenoxy)methyl)carbonyl-2,5-d
imethyl4-(4-fluorobenzy- l)piperazine.
[0317] Of this subclass of compounds, a preferred group of
compounds is- that group of compounds wherein:
[0318] R.sup.1a is one or more substituents independently selected
from the group consisting of alkyl, cycloalkyl, hydroxyalkyl,
hydroxyalkenyl, cyanoalkyl, alkoxyalkyl, monoalkylaminoalkyl,
azidoalkyl, monoalkylureidoalkyl, 30 aryloxyalkylcarbonyloxyalkyl,
and heterocyclylalkyl;
[0319] R.sup.2 is one or more substituents independently selected
from the group consisting of hydrogen, chloro or fluoro;
[0320] R.sup.3 is phenyl substituted by one or more substituents
independently selected from the group consisting of hydroxy, halo,
alkyl, alkoxy, formyl, nitro, cyano, aminoalkoxy,
cycloalkylaminoalkyl, hydroxyalkyl, (monoalkylamino)aralkyl,
alkoxyalkyl, amino, monoalkylamino, dialkylamino, monoaralkylamino,
alkylcarbonylamino, alkenylcarbonylamino, cycloalkylcarbonylamino,
arylcarbonylamino, heterocyclylcarbonylamino,
haloalkylcarbonylamino, alkoxyalkylcarbonylamino,
alkoxycarbonylalkylcarbonyiamino, alkylsulfonylamino, aminoalkyl,
monoalkylaminoalkyl, dialkylaminoalkyl, monoaralkylaminoalkyl,
alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl,
(alkylcarbonyl)(alkyl)aminoalkyl, (cycloalkyalkyl)aminoalkyl,
alkoxycarbonylalkylcarbonylaminoalkyl, alkylsulfonylaminoalkyl,
(alkylsulfonyl)(alkyl)aminoalkyl, arylsulfonylaminoalkyl,
(arylsulfonyl)(alkyl)aminoalkyl, carboxy, alkoxycarbonyl,
alkylcarbonyl, (hydroxyalkoxy)carbonyl, aminocarbonyl,
monoalkylaminocarbonyl, monoarylaminocarbonyl,
(aminocarbonylalkyl)aminocarbonyl, (aminoalkyl)aminocarbonyl,
(hydroxyalkyl)aminocarbonyl, hydroxyamidino, ureido,
monoalkylureido, monoarylureido, monoaralkylureido,
(monoalkyl)(monoaryl)ureido, (haloalkylcarbonyl)ureido,
ureidoalkyl, monoalkylureidoalkyl, dialkylureidoalkyl,
monoarylureidoalkyl, monoaralkylureidoalkyl,
monohaloalkylureidoalkyl, (haloalkyl)(alkyl)ureid- oalkyl,
(alkoxycarbonylalkyl)ureidoalkyl, glycinamido,
monoalkylglycinamido, aminocarbonylglycinamido,
(alkoxyalkylcarbonyl)glyc- inamido,
(aminocarbonyl)(alkyl)glycinamido, (alkoxycarbonylalkylcarbonyl)(-
alkyl)glycinamido, (alkoxycarbonylaminoalkylcarbonyl)glycinamido,
arylcarbonylglycinamido, (arylcarbonyl)(alkyl)glycinamido,
(monoaralkylaminocarbonyl)(alkyl)glycinamido,
(monoarylaminocarbonyl)glyc- inamido,
(monoarylaminocarbonyl)(alkyl)glycinamido, alaninamido,
heterocyclyl and heterocyclylalkyl.
[0321] Preferred compounds within this group of compounds in this
subclass group of compounds are selected from the group consisting
of the following compounds:
[0322]
1-((3,4,5-trimethoxyphenoxy)methyl)carbonyl-2-methyl4-(4-fluorobenz-
yl)piperazine;
[0323]
1-((4-chlorophenoxy)methyl)carbonyl-2-methyl4-(4-fluorobenzyl)piper-
azine;
[0324]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-ethylpiper-
azine;
[0325]
(2R)4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-propyl-
piperazine;
[0326]
(2S)4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-propyl-
piperazine;
[0327]
4-(4-fluorobenzyl)-1-(((4-chlorophenoxy)methyl)carbonyl)spiro[cyclo-
propane-1,2'-piperazine];
[0328]
1-((4-chlorophenoxy)methyl)carbonyl-2-hydroxymethyl-4-(4-fluorobenz-
yl)piperazine;
[0329]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-(2-(methox-
y)ethyl)piperazine;
[0330]
1-((4-chlorophenoxy)methyl)carbonyl-2-(2-((2-methylpropyl)amino)eth-
yl)-4-(4-fluorobenzyl)piperazine;
[0331]
1-((4-chlorophenoxy)methyl)carbonyl-3-methyl-4-(4-fluorobenzyl)pipe-
razine;
[0332]
1-((4-chlorophenoxy)methyl)carbonyl-4-(4-fluorobenzyl)-5-methylpipe-
razine;
[0333]
(2R)-1-((4-chlorophenoxy)methyl)carbonyl-3-methyl-4-(4-fluorobenzyl-
)piperazine;
[0334]
(2S)-1-((4-chlorophenoxy)methyl)carbonyl-3-methyl-4-(4-fluorobenzyl-
)piperazine;
[0335]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(hydroxyme-
thyl)piperazine;
[0336]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-hydroxy-
ethyl)piperazine;
[0337]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-(((methyl)-
ureido)methyl)piperazine;
[0338]
(2R,3R)-4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2,3--
dimethylpiperazine;
[0339]
(cis)-1-((4-chlorophenoxy)methyl)carbonyl-3,5-dimethyl-4-(4-fluorob-
enzyl)piperazine;
[0340]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-(2-(((4-ch-
lorophenoxy) -methyl)carbonyl)oxy)ethyl-5-methylpiperazine;
[0341]
(2R,5R)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl-4-(4-fluoroben-
zyl)-5-((hydroxy)methyl)piperazine;
[0342]
(2R,5R)4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-met-
hyl-5-((methoxy) -methyl)piperazine;
[0343]
(2R,5S)-4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-me-
thyl-5-( 1-methylethyl)piperazine;
[0344]
(2R,5R)4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-met-
hyl-5-( 1-hydroxyethyl)piperazine;
[0345]
(2R,5R)4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-met-
hyl-5-(1-hydroxyprop-3-enyl)piperazine;
[0346]
(2R,5S)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl4-(4-fluorobenz-
yl)-5-((cyano)methyl)piperazine;
[0347]
(2R,5R)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl-4-(4-fluoroben-
zyl)-5-(( 1,2,4-triazol-2-yl)methyl)piperazine;
[0348]
(2R,5R)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl-4-(4-fluoroben-
zyl)-5-((tetrazolyl)methyl)piperazine;
[0349]
(3S,5S)4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3,5-d-
imethylpiperazine;
[0350]
1-((4-chloro-3-nitrophenoxy)methyl)carbonyl-2-methyl-4-(4-fluoroben-
zyl)piperazine;
[0351]
(trans)-1-((4-chloro-2-methylphenoxy)methyl)carbonyl-2,5-dimethyl4--
(4-fluorobenzyl)piperazine;
[0352]
(trans)-1-((4-chloro-2-(diethylamino)phenoxy)methyl)carbonyl-2,5-di-
methyl4-(4-fluorobenzyl)piperazine;
[0353]
(trans)-1-((4-chloro-2-hydroxyphenoxy)methyl)carbonyl-2,5-dimethyl--
4-(4-fluorobenzyl)piperazine;
[0354]
(trans)-1-((5-chloro-2-methoxyphenoxy)methyl)carbonyl-2,5-dimethyl--
4-(4-fluorobenzyl)piperazine;
[0355]
(trans)-1-((4-chloro-2-((ethyl)(1-methylbutyl)aminomethyl)phenoxy)m-
ethyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0356]
1-((4-chloro-2-aminophenoxy)methyl)carbonyl-2-methyl-4-(4-fluoroben-
zyl)piperazine;
[0357]
1-((4-chloro-3-nitrophenoxy)methyl)carbonyl-2-methyl-4-(4-fluoroben-
zyl)piperazine;
[0358]
(trans)-1-((4-chloro-2-(benzylamino)phenoxy)methyl)carbonyl-2
,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0359]
(trans)-1-((4-chloro-2-((1-methylbutyl)amino)phenoxy)methyl)carbony-
l-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0360]
(trans)-1-((4-chloro-2-(iso-propylcarbonylamino)phenoxy)methyl)carb-
onyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0361]
(trans)-1-((4-chloro-2-(N'-(2,4-dichlorophenyl)ureido)phenoxy)methy-
l)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0362]
(trans)-1-((4-chloro-2-(N'-(4-nitrophenyl)ureido)phenoxy)methyl)car-
bonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0363]
(trans)-1-((4-chloro-2-(N'-(4-methylphenyl)ureido)phenoxy)methyl)ca-
rbonyl-2,5-dimethyl4-(4-fluorobenzyl)piperazine;
[0364]
(trans)-1-((4-chloro-2-(N'-benzylureido)phenoxy)methyl)carbonyl-2,5-
-dimethyl4-(4-fluorobenzyl)piperazine;
[0365]
(trans)-1-((4-chloro-2-((cyclopropylmethyl)aminomethyl)phenoxy)meth-
yl)carbonyl-2,5-dimethyl4-(4-fluorobenzyl)piperazine;
[0366]
(trans)-1-((4-chloro-2-(phenylaminomethyl)phenoxy)methyl)carbonyl-2-
,5-dimethyl4-(4-fluorobenzyl)piperazine;
[0367]
(trans)-1-((4-chloro-2-(acetylaminomethyl)phenoxy)methyl)carbonyl-2-
,5-dimethyl4-(4-fluorobenzyl)piperazine;
[0368]
(trans)-1-((4-chloro-2-((methylamino)(phenyl)methyl)phenoxy)methyl)-
carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0369]
(trans)-1-((4-chloro-2-(1-(phenylsulfonyl)(methyl)aminoethyl)phenox-
y)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0370]
(trans)-1-((4-chloro-2-(1-(acetyl)(methyl)aminoethyl)phenoxy)methyl-
)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0371]
(trans)-1-((4-chloro-2-(1-(N-methyl--N'-ethylureido)ethyl)phenoxy)m-
ethyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0372]
(trans)-1-((4-chloro-2-(1-((methyl)(ethyl)amino)ethyl)phenoxy)methy-
l)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0373]
(trans)-1-((4-chloro-2-(1-(dimethylamino)ethyl)phenoxy)methyl)carbo-
nyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0374]
(2R)-1-((4-chloro-2-((4-t-butoxycarbonylpiperazin-1-yl)methyl)pheno-
xy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine;
[0375]
(trans)-1-((4-chloro-2-((piperazin-1-yl)methyl)phenoxy)methyl)carbo-
nyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0376]
(trans)-1-((4-chloro-2-(oxazol-2-ylaminomethyl)phenoxy)methyl)carbo-
nyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0377]
1-((4-chloro-2-(morpholin-4-ylmethyl)phenoxy)methy)carbonyl-2-methy-
l-4-(4-fluorobenzyl)piperazine;
[0378]
(trans)-1-((4-bromo-2-formylphenoxy)methyl)carbonyl-2,5-dimethyl4-(-
4-fluorobenzyl)piperazine;
[0379]
(trans)-1-((4-fluoro-3-chlorophenoxy)methyl)carbonyl-2,5-dimethyl4--
(4-fluorobenzyl)piperazine;
[0380]
1-((4-chloro-2-methoxycarbonylphenoxy)methyl)carbonyl-2-methyl-4-(4-
-fluorobenzyl)piperazine;
[0381]
(trans)-1-((4-chloro-2-methoxycarbonylphenoxy)methyl)carbonyl-2,5-d-
imethyl4-(4-fluorobenzyl)piperazine;
[0382]
1-((4-chloro-2-aminocarbonylphenoxy)methyl)carbonyl-2-methyl4-(4-fl-
uorobenzyl)piperazine;
[0383]
(trans)-1-((4-chloro-2-carboxyphenoxy)methyl)carbonyl-2,5-dimethyl4-
-(4-fluorobenzyl)piperazine;
[0384]
(trans)-1-((4-chloro-2-formylphenoxy)methyl)carbonyl-2,5-dimethyl-4-
-(4-fluorobenzyl)piperazine;
[0385]
(trans)-1-((4-chloro-2-cyanophenoxy)methyl)carbonyl-2,5-dimethyl-4--
(4-fluorobenzyl)piperazine;
[0386]
(trans)-1-((3-cyanophenoxy)methyl)carbonyl-2,5-dimethyl4-(4-fluorob-
enzyl)piperazine;
[0387]
(trans)-1-((4-methyl-2-aminophenoxy)methyl)carbonyl-2,5-dimethyl4-(-
4-fluorobenzyl)piperazine;
[0388]
(trans)-1-((3-formylphenoxy)methyl)carbonyl-2,5-dimethyl-4-(4-fluor-
obenzyl)piperazine;
[0389]
(trans)-1-((4-methyl-2-acetylphenoxy)methyl)carbonyl-2,5-dimethyl-4-
-(4-fluorobenzyl)piperazine;
[0390] (trans)-1-((2-methoxycarbonylphenoxy)methyl)carbonyl-2,5-d
imethyl-4-(4-fluorobenzyl)piperazine;
[0391]
(trans)-1-((3-nitrophenoxy)methyl)carbonyl-2,5-dimethyl-4-(4-fluoro-
benzyl)piperazine;
[0392]
(trans)-1-((4-acetyl-2-(aminocarbonyl)phenoxy)methyl)carbonyl-2,5-d-
imethyl4-(4-fluorobenzyl)piperazine;
[0393]
(trans)-1-((4-nitro-3-methylphenoxy)methyl)carbonyl-2,5-dimethyl-4--
(4-fluorobenzyl)piperazine;
[0394]
(trans)-1-((5-nitro-2-methylphenoxy)methyl)carbonyl-2,5-dimethyl-4--
(4-fluorobenzyl)piperazine;
[0395]
(trans)-1-((4-amino-3-nitrophenoxy)methyl)carbonyl-2,5-dimethyl4-(4-
-fluorobenzyl)piperazine;
[0396]
(trans)-1-((5-nitro-2-aminophenoxy)methyl)carbonyl-2,5-dimethyl-4-(-
4-fluorobenzyl)piperazine;
[0397]
(trans)-1-((2-aminophenoxy)methyl)carbonyl-2,5-dimethyl4-(4-fluorob-
enzyl)piperazine;
[0398]
(trans)-1-((3-methoxyphenoxy)methyl)carbonyl-2,5-dimethyl4-(4-fluor-
obenzyl)piperazine;
[0399]
(trans)-1-((4-methoxy-2-acetylphenoxy)methyl)carbonyl-2,5-dimethyl4-
-(4-fluorobenzyl)piperazine;
[0400]
(trans)-1-((5-methoxy-2-acetylphenoxy)methyl)carbonyl-2,5-dimethyl--
4-(4-fluorobenzyl)piperazine;
[0401]
(trans)-1-((2-((2-hydroxyethyl)aminocarbonyl)phenoxy)methyl)carbony-
l-2,5-dimethyl4-(4-fluorobenzyl)piperazine;
[0402]
(trans)-1-((2-((2-hydroxyethoxy)carbonyl)phenoxy)methyl)carbonyl-2,-
5-dimethyl4-(4-fluorobenzyl)piperazine;
[0403]
(trans)-1-((2-(2-hydroxyethoxy)phenoxy)methyl)carbonyl-2,5-dimethyl-
-4-(4-fluorobenzyl)piperazine;
[0404]
(trans)-1-((2-acetyl4,5-dimethylphenoxy)methyl)carbonyl-2,5-dimethy-
l-4-(4-fluorobenzyl)piperazine;
[0405]
(trans)-1-((5-methoxy-2-(methoxycarbonyl)phenoxy)methyl)carbonyl-2,-
5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0406]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-(N'-methyl-
ureido)-amino)methyl)piperazine;
[0407]
(trans)-1-((4-methyl-2-formylphenoxy)methyl)carbonyl-2,5-dimethyl-4-
-(4-fluorobenzyl)piperazine;
[0408]
(trans)-1-((3-chloro-5-methoxyphenoxy)methyl)carbonyl-2,5-dimethyl--
4-(4-fluorobenzyl)piperazine;
[0409]
(trans)-1-((2-methoxy-5-nitrophenoxy)methyl)carbonyl-2,5-dimethyl-4-
-(4-fluorobenzyl)piperazine;
[0410]
(trans)-1-((2-(hydroxymethyl)phenoxy)methyl)carbonyl-2,5-dimethyl-4-
-(4-fluorobenzyl)piperazine;
[0411]
(trans)-1-((2-methylphenoxy)methyl)carbonyl-2,5-dimethyl-4-(4-fluor-
obenzyl)piperazine;
[0412]
1-((4-chlorophenoxy)methyl)carbonyl-2-(2-azidoethyl)-4-(4-fluoroben-
zyl)piperazine;
[0413]
(trans)-1-((4-chloro-2-(phthalimido)phenoxy)methyl)carbonyl-2,5-dim-
ethyl-4-(4-fluorobenzyl)piperazine;
[0414]
(trans)-1-((4-chloro-2-(maleimido)phenoxy)methyl)carbonyl-2,5-dimet-
hyl-4-(4-fluorobenzyl)piperazine;
[0415]
(trans)-1-((4-chloro-2-((4-(benzylcarbonyl)piperazin-1-yl)methyl)ph-
enoxy)methyl)-carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0416]
(trans)-1-((4-chloro-2-((4-((2,3,4-trifluorophenyl)aminocarbonyl)pi-
perazin-1-yl)methyl)phenoxy)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl-
)piperazine;
[0417]
(trans)-1-((4-chloro-2-((4-((2-fluorophenyl)aminocarbonyl)piperazin-
-1-yl)methyl)phenoxy)methyl)carbonyl-2,5-dimethyl4-(4-fluorobenzyl)piperaz-
ine;
[0418]
(trans)-1-((4-chloro-2-((NU-(2,6-difluorophenyl)ureido)phenoxy)meth-
yl)carbonyl-2,5-dimethyl4-(4-fluorobenzyl)piperazine;
[0419]
(trans)-1-((4-chloro-2-(ethenylcarbonylamino)phenoxy)methyl)carbony-
l-2,5-dimethyl4-(4-fluorobenzyl)piperazine;
[0420]
(trans)-1-((4-chloro-2-(cyclopropylcarbonylamino)phenoxy)methyl)car-
bonyl-2,5-dimethyl4-(4-fluorobenzyl)piperazine;
[0421]
(trans)-1-((4-chloro-2-(cyclopentylcarbonylamino)phenoxy)methyl)car-
bonyl-2,5-dimethyl4-(4-fluorobenzyl)piperazine;
[0422]
(trans)-1-((4-chloro-2-((furan-2-yl)carbonylamino)phenoxy)methyl)ca-
rbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0423]
(trans)-1-((4-chloro-2-(phenylcarbonylamino)phenoxy)methyl)carbonyl-
-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0424]
(trans)-1-((4-chloro-2-((N'-(3-methoxyphenyl)ureido)phenoxy)methyl)-
carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0425]
(trans)-1-((4-chloro-2-((N'-(methoxycarbonylmethylcarbonyl)-N'-(met-
hyl)glycinamido)phenoxy)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)pip-
erazine;
[0426]
(trans)-1-((4-chloro-2-((N'-(2-methoxycarbonylethyl)carbonyl-N'-(me-
thyl)glycinamido)phenoxy)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)pi-
perazine;
[0427]
(trans)-1-((4-chloro-2-((N'-(3-methylbenzyl)aminocarbonyl-N'-(methy-
l)glycinamido)phenoxy)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piper-
azine;
[0428]
(trans)-1-((4-chloro-2-((N'-(3-trifluoromethyl-4-fluorophenyl)carbo-
nyl--N'-(methyl)glycinamido)phenoxy)methyl)carbonyl-2,5-dimethyl4-(4-fluor-
obenzyl)piperazine;
[0429]
(trans)-1-((4-chloro-2-((N'-(4-methylbenzyl)aminocarbonyl-N'-(methy-
l)glycinamido)phenoxy)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piper-
azine;
[0430]
(trans)-1-((4-chloro-2-((N'-(3-chlorophenyl)carbonyl-N'-(methyl)gly-
cinamido)phenoxy)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine-
;
[0431]
(trans)-1-((4-chloro-2-((N'-(4-fluorobenzyl)aminocarbonyl-N'-(methy-
l)glycinamido)phenoxy)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piper-
azine;
[0432]
(trans)-1-((4-chloro-2-(N'-(2-iodophenylcarbonyl)glycinamido)phenox-
y)methyl)carbonyl-2,5-dimethyl4-(4-fluorobenzyl)piperazine;
[0433]
(trans)-1-((4-chloro-2-(N'-(2,3-difluorophenylcarbonyl)glycinamido)-
phenoxy)-methyl)carbonyl-2,5-dimethyl4-(4-fluorobenzyl)piperazine;
[0434]
(trans)-1-((4-chloro-2-(N'-((4-phenoxyphenyl)aminocarbonyl)glycinam-
ido)phenoxy)-methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0435]
(trans)-1-((4-chloro-2-(N'-(2,4-diflurophenylcarbonyl)glycinamido)p-
henoxy)methyl)-carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0436] (trans)-1-((4-chloro-2-((2-iodophenylcarbonyl)am
inomethyl)phenoxy)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazi-
ne;
[0437]
(trans)-1-((4-chloro-2-((ethoxycarbonylmethylcarbonyl)aminomethyl)p-
henoxy)-methyl)carbonyl-2,5-dimethyl4-(4-fluorobenzyl)piperazine;
[0438]
(trans)-1-((4-chloro-2-(N'-(3-chloropropyl)ureidomethyl)phenoxy)met-
hyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0439]
(trans)-1-((4-chloro-2-(N'-(2-fluoro-6-trifluoromethylphenyl)ureido-
methyl)phenoxy)-methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0440]
(trans)-1-((4-chloro-2-((3-fluorophenyl)carbonylaminomethyl)phenoxy-
)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0441]
(trans)-1-((4-chloro-2-(N'-(2-(ethoxycarbonyl)ethyl)ureidomethyl)ph-
enoxy)-methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0442]
(2S)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-f-
luorobenzyl)piperazine;
[0443]
(trans)-1-((4-chloro-2-((2,5-di(trifluoromethyl)phenyl)carbonylamin-
omethyl)-phenoxy)methyl)carbonyl-2,5-dimethyl4-(4-fluorobenzyl)piperazine;
and
[0444]
(trans)-1-((4-chloro-2-(N'-(2-(phenyl)cyclopropyl)ureidomethyl)phen-
oxy)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine.
[0445] A more preferred group of compounds in this subclass group
of compounds are those compounds wherein:
[0446] R.sup.1a is one or more substituents independently selected
from the group consisting of alkyl and hydroxyalkyl;
[0447] R.sup.2 is one or more substituents independently selected
from the group consisting of hydrogen, chloro or fluoro;
[0448] R.sup.3 is phenyl substituted by one or more substituents
independently selected from the group consisting of halo, alkyl,
alkoxy, formyl, nitro, cycloalkylaminoalkyl, hydroxyalkyl, amino,
alkylcarbonylamino, haloalkylcarbonylamino,
alkoxyalkylcarbonylamino, alkoxycarbonylalkylcarbonylamino,
alkylsulfonylamino, aminoalkyl, monoalkylaminoalkyl,
dialkylaminoalkyl, (alkylsulfonyl)(alkyl)aminoalkyl, alkylcarbonyl,
aminocarbonyl, monoalkylaminocarbonyl, monoarylaminocarbonyl,
(aminocarbonylalkyl)aminocarbonyl, (aminoalkyl)aminocarbonyl,
hydroxyamidino, ureido, (haloalkylcarbonyl)ureido, ureidoalkyl,
glycinamido, monoalkylglycinamido, aminocarbonylglycinamido,
(alkoxyalkylcarbonyl)glyc- inamido,
(aminocarbonyl)(alkyl)glycinamido, (alkoxycarbonylaminoalkylcarbo-
nyl)glycinamido, alaninamido, and heterocyclylalkyl.
[0449] Preferred compounds within this more preferred group of
compounds in this subclass group of compounds are selected from the
group consisting of the following compounds:
[0450]
(trans)-1-((4-chloro-3-nitrophenoxy)methyl)carbonyl-2,5-dimethyl-4--
(4-fluorobenzyl)piperazine;
[0451]
(trans)-1-((4-chloro-2-(hydroxymethyl)phenoxy)methyl)carbonyl-2,5-d-
imethyl-4-(4-fluorobenzyl)piperazine;
[0452]
(trans)-1-((4-chloro-2-(aminocarbonyl)phenoxy)methyl)carbonyl-2,5-d-
imethyl4-(4-fluorobenzyl)piperazine;
[0453]
(2R,5S)-1-((4-chloro-2-(aminocarbonyl)phenoxy)methyl)carbonyl-2,5-d-
imethyl-4-(4-fluorobenzyl)piperazine;
[0454]
(2S,5R)-1-((4-bromo-3,5-dimethoxyphenoxy)methyl)carbonyl-2,5-dimeth-
yl-4-(4-fluorobenzyl)piperazine;
[0455]
(2R,5S)-1-((3-hydroxy-5-methylphenoxy)methyl)carbonyl-2,5-dimethyl--
4-(4-fluorobenzyl)piperazine;
[0456]
(2S,5R)-1-((4-nitro-3-formylphenoxy)methyl)carbonyl-2,5-dimethyl-4--
(4-fluorobenzyl)piperazine;
[0457]
(2R)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl-
)piperazine;
[0458]
4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-(2-hydroxy-
ethyl)piperazine;
[0459]
(trans)4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2,5-d-
imethylpiperazine;
[0460]
(2R,5S)4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2,5-d-
imethylpiperazine;
[0461]
(trans)-1-((4-chloro-3,5-dimethoxyphenoxy)methyl)carbonyl-2,5-dimet-
hyl4-(4-fluorobenzyl)piperazine;
[0462]
(2R,5S)-1-((4-chloro-3,5-dimethoxyphenoxy)methyl)carbonyl-2,5-dimet-
hyl-4-(4-fluorobenzyl)piperazine;
[0463]
(2R,5S)4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2-(2--
hydroxyethyl)-5-methylpiperazine;
[0464]
(2R,6R)-4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-2,6--
dimethylpiperazine;
[0465]
(trans)-1-((4-chloro-2-methoxyphenoxy)methyl)carbonyl-2,5-dimethyl--
4-(4-fluorobenzyl)piperazine;
[0466]
1-((4-chloro-2-(hydroxymethyl)phenoxy)methyl)carbonyl-2-methyl-4-(4-
-fluorobenzyl)piperazine;
[0467]
(2R,5S)-1-((4-chloro-3-(hydroxymethyl)phenoxy)methyl)carbonyl-2,5-d-
imethyl-4-(4-fluorobenzyl)piperazine;
[0468]
(trans)-1-((4-chloro-2-(1-hydroxyethyl)phenoxy)methyl)carbonyl-2,
5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0469]
(trans)-1-((4-chloro-2-(aminomethyl)phenoxy)methyl)carbonyl-2,5-dim-
ethyl-4-(4-fluorobenzyl)piperazine;
[0470]
(trans)-1-((4-chloro-2-(ureidomethyl)phenoxy)methyl)carbonyl-2,5-di-
methyl-4-(4-fluorobenzyl)piperazine;
[0471]
(trans)-1-((4-chloro-2-aminophenoxy)methyl)carbonyl-2,5-dimethyl-4--
(4-fluorobenzyl)piperazine;
[0472]
1-((4-chloro-2-(acetylamino)phenoxy)methyl)carbonyl-2-methyl-4-(4-f-
luorobenzyl)piperazine;
[0473]
(trans)-4-(4-fluorobenzyl)-1-((2-acetylamino-4-chlorophenoxy)methyl-
)carbonyl-2,5-dimethylpiperazine;
[0474]
(trans)-1-((4-chloro-2-(propylcarbonylamino)phenoxy)methyl)carbonyl-
-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0475]
(trans)-1-((4-chloro-2-(methoxymethylcarbonylamino)phenoxy)methyl)c-
arbonyl-2,5-dimethyl4-(4-fluorobenzyl)piperazine;
[0476]
(trans)-1-((4-chloro-2-(2-(methoxycarbonyl)ethylcarbonylamino)pheno-
xy)-methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0477]
(trans)-1-((4-chloro-2-(2-(ethoxycarbonyl)ethylcarbonylamino)phenox-
y)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0478]
(trans)-1-((4-chloro-2-(methylsulfonylamino)phenoxy)methyl)carbonyl-
-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0479]
(trans)-1-((4-chloro-2-(bromomethylcarbonylamino)phenoxy)methyl)car-
bonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0480]
(2R)-1-((4-chloro-2-(glycinamido)phenoxy)methyl)carbonyl-2-methyl4--
(4-fluorobenzyl)piperazine;
[0481]
(trans)-1-((4-chloro-2-((N'-methylglycinamido)phenoxy)methyl)carbon-
yl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0482]
(trans)-1-((4-chloro-2-(alaninamido)phenoxy)methyl)carbonyl-2,5-dim-
ethyl-4-(4-fluorobenzyl)piperazine;
[0483]
(trans)-1-((4-chloro-2-((aminocarbonyl)glycinamido)phenoxy)methyl)c-
arbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0484]
(trans)-1-((4-chloro-2-((aminocarbonyl)(methyl)glycinamido)phenoxy)-
methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0485]
(trans)-1-((4-chloro-2-(N'-ethyluredio)phenoxy)methyl)carbonyl-2,5--
dimethyl-4-(4-fluorobenzyl)piperazine;
[0486]
(trans)-1-((4-chloro-2-(ethylcarbonylamino)phenoxy)methyl)carbonyl--
2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0487]
(trans)-1-((4-chloro-2-amino-5-nitrophenoxy)methyl)carbonyl-2,5-dim-
ethyl-4-(4-fluorobenzyl)piperazine, dihydrochloride salt;
[0488]
(trans)-1-((4-chloro-2-(((ethyl)amino)methyl)phenoxy)methyl)carbony-
l-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0489]
(trans)-1-((4-chloro-2-(((diethyl)amino)methyl)phenoxy)methyl)carbo-
nyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0490]
(trans)-1-((4-chloro-2-(((cyclopropyl)amino)methyl)phenoxy)methyl)c-
arbonyl-2,5-dimethyl-4-(4- fluorobenzyl)piperazine;
[0491]
(trans)-1-((4-chloro-2-(((dimethyl)amino)methyl)phenoxy)methyl)carb-
onyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0492]
(trans)-1-((4-chloro-2-(((methyl)amino)methyl)phenoxy)methyl)carbon-
yl-2,5-dimethyl-4-(4- fluorobenzyl)piperazine;
[0493]
(trans)-1-((4-chloro-2-((amino)methyl)phenoxy)methyl)carbonyl-2,5-d-
imethyl-4-(4-fluorobenzyl)piperazine;
[0494]
(trans)-1-((4-chloro-2-((4-methylpiperazin-1-yl)methyl)phenoxy)meth-
yl)carbonyl-2,5-dimethyl4-(4-fluorobenzyl)piperazine;
[0495]
(trans)-1-((4-chloro-2-((piperazin-1-yl)methyl)phenoxy)methyl)carbo-
nyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0496]
(trans)-1-((4-chloro-2-(ethylaminomethyl)phenoxy)methyl)carbonyl-2,-
5-dimethyl4-(4-fluorobenzyl)piperazine;
[0497]
(trans)-1-((4-chloro-2-(1-(methylamino)ethyl)phenoxy)methyl)carbony-
l-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0498]
(trans)-1-((4-chloro-2-(1-(methylsulfonyl)(methyl)aminoethyl)phenox-
y)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0499]
(2R)-1-((4-chloro-2-((piperazin-1-yl)methyl)phenoxy)methyl)carbonyl-
-2-methyl-4-(4-fluorobenzyl)piperazine;
[0500]
(2R,5S)-1-((4-chloro-2-((piperazin-1-yl)methyl)phenoxy)methyl)carbo-
nyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0501]
(trans)-1-((4-chloro-2-((4-t-butoxycarbonylpiperazin-1-yl)methyl)ph-
enoxy)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0502]
(trans)-1-((4-chloro-2-(imidazol-1-ylmethyl)phenoxy)methyl)carbonyl-
-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0503]
(trans)-1-((4-chloro-2-(1-(imidazol-1-yl)ethyl)phenoxy)methyl)carbo-
nyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0504]
(trans)-1-((4-chloro-2-(triazol-1-ylmethyl)phenoxy)methyl)carbonyl--
2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0505]
(trans)-1-((4-chloro-2-(tetrazol-1-ylmethyl)phenoxy)methyl)carbonyl-
-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0506]
(trans)-1-((4-chloro-2-((morpholin4-yl)methyl)phenoxy)methyl)carbon-
yl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0507]
(2R)-1-((4-chloro-2-aminocarbonylphenoxy)methyl)carbonyl-2-methyl-4-
-(4-fluorobenzyl)piperazine;
[0508]
1-((4-chloro-2-formylphenoxy)methyl)carbonyl-2-methyl4-(4-fluoroben-
zyl)piperazine;
[0509]
(2R,5S)-1-((4-chloro-2-formylphenoxy)methyl)carbonyl-2,5-dimethyl-4-
-(4-fluorobenzyl)piperazine;
[0510]
(2R)-1-((4-chloro-2-formylphenoxy)methyl)carbonyl-2-methyl4-(4-fluo-
robenzyl)piperazine;
[0511]
(trans)-1-((4-chloro-2-(methylaminocarbonyl)phenoxy)methyl)carbonyl-
-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0512]
(trans)-1-((4-chloro-2-((aminocarbonylmethyl)aminocarbonyl)phenoxy)-
methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0513]
(trans)-1-((4-chloro-2-((2-aminoethyl)aminocarbonyl)phenoxy)methyl)-
carbonyl-2,5-dimethyl4-(4-fluorobenzyl)piperazine;
[0514]
(trans)-1-((4-chloro-2-((4-aminocarbonylphenyl)aminocarbonyl)phenox-
y)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0515]
(trans)-1-((4-chloro-2-(hydroxyamidino)phenoxy)methyl)carbonyl-2,5--
dimethyl4-(4-fluorobenzyl)piperazine;
[0516]
(trans)-1-((4-chloro-2-acetylphenoxy)methyl)carbonyl-2,5-dimethyl-4-
-(4-fluorobenzyl)piperazine;
[0517]
(trans)-1-((2-(aminocarbonyl)phenoxy)methyl)carbonyl-2,5-dimethyl-4-
-(4-fluorobenzyl)piperazine;
[0518]
(trans)-1-((4-chloro-2-((N'-(trichloromethylcarbonyl)ureido)phenoxy-
)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
[0519]
(trans)-1-((4-chloro-2-(N'-(methoxymethylcarbonyl)glycinamido)pheno-
xy)methyl)-carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine;
and
[0520]
(trans)-1-((4-chloro-2-(N'-(ethoxycarbonylaminocarbonyl)-glycinamid-
o)phenoxy)methyl)carbonyl-2,5-dimethyl-4-(4-fluorobenzyl)piperazine.
[0521] The most preferred group of compounds within this subclass
group of compounds are those compounds wherein R.sup.2 is 4-fluoro
and R.sup.3 is phenyl substituted at the 4-position with chloro and
at the 2-position by aminocarbonyl, ureido, or glycinamido.;
namely, the compounds selected from the group consisting of the
following compounds:
[0522]
(2R,5S)-1-((4-chloro-2-(aminocarbonyl)phenoxy)methyl)carbonyl-2,5-d-
imethyl-4-(4-fluorobenzyl)piperazine;
[0523]
(trans)-1-((4-chloro-2-(glycinamido)phenoxy)methyl)carbonyl-2,5-dim-
ethyl4-(4-fluorobenzyl)piperazine;
[0524]
(2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-f-
luorobenzyl)piperazine;
[0525]
(trans)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2,5-dimethyl-
-4-(4-fluorobenzyl)piperazine;
[0526]
(2R,5S)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2,5-dimethyl-
-4-(4-fluorobenzyl)piperazine; and
[0527]
(2R,5S)-1-((4-chloro-2-(glycinamido)phenoxy)methyl)carbonyl-2,5-dim-
ethyl4-(4-fluorobenzyl)piperazine.
[0528] The most preferred compound is
(2R)-1-((4-chloro-2-(ureido)phenoxy)-
methyl)carbonyl-2-methyl4-(4-fluorobenzyl)piperazine.
EXAMPLES
Example 1
[0529] Following the Testing Procedures outlined above, the heart
weight to body weight ratio (H/B) of sacrificed rats was measured
and histological examination and echocardiograms were performed to
evaluate the severity of the disease. Myocarditis-affected areas in
the treated groups were suppressed compared to those in the control
groups (group B.times.0 or group B.times.14 vs controls: area
ratio; 1.0.+-.1.1% vs 51.8.+-.8.3% or 11.8.+-.2.9% vs 52.4.+-.9.3%
respectively P<0.05). Cardiac function in the treated groups was
improved (group B.times.0 or group B.times.14 vs controls: FS;
46.7.+-.3.6% vs 20.8.+-.2.6% or 39.4.+-.4.1% vs 22.0.+-.5.9%,
respectively P<0.05). H/B showed similar reduction in the
treated groups. The CCR1 antagonist reduced the severity of
EAM.
* * * * *